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

Welcome all, and thank you for joining us today for this virtual event on Bardet-Biedl syndrome. I'm David Meeker, Chairman, President, and Chief Executive Officer of Rhythm Pharmaceuticals. Before we get started, we want to alert you that we will be making forward-looking statements, which represent our views only as of today, and I encourage you to review this statement in our SEC filings, which are available on our website. So this is a really exciting moment for us as we prepare to launch IMCIVREE in the United States for patients with Bardet-Biedl syndrome pending, of course, FDA approval. This will be by far our most significant milestone to date as we work to develop IMCIVREE or setmelanotide for a number of genetic and nongenetically-driven defects in the melanocortin pathway. We're extremely fortunate to have 3 wonderful guest speakers with us today: Mary Morris, Mary and her husband are parents to 6 children, including Ashley, who is 28 and Carly who is 21, both of whom are diagnosed and living with Bardet-Biedl syndrome. Second is Dr. Rushika Conroy, a pediatric endocrinologist at Baystate Children's Hospital in Springfield, Massachusetts, where she also serves as Medical Director for Baystate's pediatric weight management program and its pediatric type 2 diabetes program, and she is an Associate Professor of Pediatrics at the University of Massachusetts Medical School. And finally, we have Dr. Robert Haws, the Director of the Clinical Research Center at the Marshfield Clinic Research Institute and Director of the Center of Excellence for Bardet-Biedl syndrome. Also today, you're going to hear from Jennifer Chien, sitting on my right, and who's Executive Vice President for North America at Rhythm; and Sarah Ryan, Vice President of Sales and Marketing. Both Jennifer and Sarah joined Rhythm approximately a year ago to build out our commercial and community building teams with a major focus on Bardet-Biedl syndrome. Hunter Smith, our CFO, is here today as well, and he will participate in our Q&A. So the format for today is we'll have Mary, Rushika and Bob speak during the first half of the event. And following Bob's remarks, we'll spend a few minutes on Q&A. For the questions, we ask that you submit them through the chat function available on the web page during this live event, and we'll pull them through as best and as quickly as we can. So following the Q&A with our guest speakers, Jennifer and Sarah will provide details on our commercial organization, the activities to date and the patient finding efforts and results. And then we'll follow Sarah's presentation with a second Q&A specific to our commercial readiness. So next slide. So this is a slide that I think many of you have seen, it's a slide we used to frame Rhythm and you start with the top sentence, which is basically our mission statement, transforming the care of patients with rare genetic diseases of obesity. And it's an important statement. It speaks to a very important point of distinction, which is we're not pursuing a drug for obesity per se. We're very much focused on the rare genetic diseases where obesity is a consequence. As you know, we had IMCIVREE approved in November 2020 and subsequently in mid-July 2021 in the EMEA. So the 3 buckets on the bottom, on the left on the commercial availability, we'll be speaking to that experience on our March 1 earnings call as we will the third bucket on the right, which is the -- our robust clinical efforts to expand and -- understand and then expand the addressable patient population that can be served by a targeted therapy like IMCIVREE. But today, we're focused on the middle bucket, which is Bardet-Biedl and the first half of this program will be hopefully educating you as we hear Mary's story and subsequently from our 2 experts, Dr. Conroy and Dr. Haws as to the severe, significant unmet medical need here and how setmelanotide may be able to provide a significant benefit to those patients. Next slide. We think we're ready. We've got an accelerated PDUFA date. We expected an accelerated review with a 6-month review. It came through with a 4-month review, which was a little less time than we thought we had. But I think you're going to hear today that we've made a tremendous amount of progress, and we feel really good about where we are. Any launch starts with a good strong understanding of the unmet medical need and the first half of the program, we'll speak to that. Dr. Haws will take us through some of the data that supports the fact that IMCIVREE may be a very good solution for these patients. And then in the second half of the program we'll dive into our commercial launch readiness and give you a lot more color around where we are to date, all of which prepares us for that PDUFA date on March 16. So with that, I'm thrilled to turn it over to Mary. As I mentioned, Mary has 2 children, now adults, who are living with Bardet-Biedl syndrome and the obesity and hyperphagia that comes with it. She's a prominent advocate in the BBS community involved with the BBS Foundation and Family Association. In this past fall, Mary delivered an aspiring presentation to all of us at Rhythm, and she was very gracious to agree to join us again today. So with that, I'll turn it over to you, Mary.

Thank you. Good afternoon. My name is Mary Morris, and I'm here to share a little bit about our live with Bardet-Biedl syndrome. More specifically, the impact hyperphagia and obesity has had on our 2 daughters. My 2 youngest girls have BBS10. Next slide, please. One more. Thank you. The pictures here are of Ashley and Carly. The girls are a little bit older now than in these pictures. Ashley is in the gray shirt on the right, she's 28. And Carly is 21. Both of my girls love singing to musicals and watching Disney movies. They're both Pokémon Masters and they love everything Manga. They both love cats and want to work at the cat shelter here once the pandemic ends. Carly wants to be an artist when she grows up and Ashley like to be a writer. They also both have the normal expression of BBS, legal blindness, developmental and learning delays, kidney issues leading to transplant for Ashley and they're both obese. Next slide, please. Both my girls had a normal birthweight and begin to gain weight rapidly as infants. Ashley was born with significant kidney failure and she needed a dialysis at birth, Carly had normal kidneys at birth. So this is a picture of their growth curves. It's a picture of the growth curves from birth age to 3, the top set of curves represent the length and the bottom set of curves is the weight. I only have marked the weight on these charts. There's an arrow pointing to the 95th percentile on the chart on the left. Ashley was 8.5 pounds at birth and her weight quickly tracked up to the 95th percentile even with kidney failure when you would expect weight gain to be very slow at this time. By 18 -- rather by 15 months, her weight was off the top of the chart. Carly was born 7 years later. She only weighed 6 pounds at birth, but she very rapidly gained weight. And by 5 months was above the 95th percentile. Carly weighed 45 pounds when she was 3 years old. And you can see that point on the right-hand chart all the way up in the length chart. The average child is about 30 pounds at 3. Ashley was clinically diagnosed with BBS when she was 18 months old. And I remember when they told us that people with BBS are blind and obese. And I was instantly devastated by the thought of my child who's going to lose her vision, but I was sure that she would never be obese. I had all the kids who were thin, and I knew how to feed children. And from what I've been told by other parents, this is exactly what they go through as well. Obesity is the one area of BBS that all parents think that we're going to be able to take control of. But quickly, we realize that it's not in our control at all. Next slide. These are my girls when they were babies. Ashley is on the left and Carly is on the right. I love to see people's reaction to my babies. Everyone loves a chubby baby. However, reactions from public changes as the girls get older. While everyone delights in a chubby baby, no one is delighted by a chubby middle school or a high school aged child. Next slide, please. So at about this time, I started bringing my older kids with me when we go to doctor appointments. It seemed like every appointment focused on their weight at some point. And I brought the older standard kids along kind of to try to prove that I wasn't purposely making my babies fat. Next slide. Here the girls are again, Carly is on the left and Ashley is on the right. Carly is heading off to kindergarten, we went on a hike and Ashley is sitting in the yard, she's looking at a bird. And you can tell from this picture that they're already both pretty large. At this weight, they can't run and play at recess like the other kids. They can't see well enough to do most sports and development only. They just don't understand why exercise is a good thing. Next slide. Obesity affects all parts of their lives. When they were babies, they outgrew their car seats before they were a year old. We were able to get a larger car seat once they were older, but as babies, they had to ride around in seats that were too small for their weight and too tight to be comfortable, and I knew they wouldn't be safe if we've had an accident. And they also had to have wheelchairs rather than strollers because the stroller stops working, once a child reaches about 50 pounds, the wheels just don't turn anymore, that a 50-pound 3-year-old can't walk everywhere and they were way too heavy to be carried. Next slide. It was impossible to find school age or rather age-appropriate shoes or clothing for them once they got into the school age range. At 4, they were wearing adult size clothing that were in the plus sizes. It's impossible to find uniforms if you have a uniform school for 100 pound 7-year-old. Ashley is in the middle. She's wearing a donation shirt. She's getting ready to go out to kindergarten in her adult size donation shirt. And Carly would often wear dresses because it is the only thing that would cover her tummy besides maternity shirts and they would wear capri pants because they were available in plus sizes, but I didn't have to hem them. Next slide. Now [Technical Difficulty] is more exhausting in our house, just being around food was so stressful that they would often melt down into a tantrum as I was preparing it. While they were always hungry, they were also very picky. So if the food wasn't just right, they'd start to cry. I carried bread and peanut butter in my purse for years when we ate out because I knew that this would stop them from having a tantrum at least until they'd eaten a sandwich and wanted more. We rarely went out to eat -- I'm sorry, go back one, if you could. We rarely went out to eat because they'd see what other people had and they wanted to eat what they had on their plates as well. Our family learned that we had to eat our food as fast as we could because the girls would inhale their food and then try to get the food on our plates. If they wanted it, they'd try to get it. And if they didn't get it, they would cry until we gave in. They're just driven to eat. They'll eat breakfast and then immediately ask about lunch. They have to eat all 3 meals every day, breakfast, then lunch then dinner, even if they sleep late and miss breakfast. We hide food and keep the refrigerator door locked. Our 3 older kids didn't need food restrictions but had to live that life. It was hard for them, and it was embarrassing at times, especially if we were out in public. My girls can eat an entire box of cereal or crackers if I'm not watching. They'll eat the salad with peanut butter I give them as a healthy snack and then sneak below for bread later when I'm not looking. I package their food in serving size portions and this really upsets them because they always want the biggest piece and the single serving is never the biggest piece. There's never been a time when they say that they're full or when they turn down a chance to eat. Next slide, please. As children, they struggle every day because their focus was so fixed on what the next snack or meal or dessert would be that they couldn't attend to school work or play. They wanted to talk about and plan foods to cook and talk about how delicious the food was going to be. They make menus and grocery list of things they wanted to eat and they make plans for parties far in the future and then research recipes online. This is a picture of the kids after Ashley had her kidney transplant. Our older kids had come home to visit and we'd gone to Sedona for the day. And the older kids were very pleased to be together, and they are focused on each other. And Ashley was focused on her treat. She's holding a piece of rock candy there. I included this visual because it's so typical of the BBS child. I could replace her face with virtually any other kid I know with BBS, and the picture would still be accurate. It's hard for our girls to form and support relationships with others because their single focus is on food. Next slide. When people learned that my girls were going to be blind, they felt terrible for us and for them. Thankfully, there are many services available to the child with visual impairment. They started braille and cane training in kindergarten. There are programs in place to teach them how to live well with blindness. We were assured that they would live a full life with vision loss, and that there was nothing that we could have done to stop it from happening. Next slide. When Ashley's kidneys failed, she went on dialysis and services were offered to get her through to transplant. She's had her transplanted kidney for 19 years, and she's living a good life with her transplant. We were commended for taking such good care of her kidneys. We were made to feel that there's nothing we could do to stop this failure from happening. And this is a picture when Ashley was a baby. She has just gone off dialysis. And on the right, she's going back on dialysis. The machine sitting next to her on the table is called the cycler and she'd be hooked up to the cycler for 12 hours a day. Next slide. But as my girls became obese, there were no services in place to treat this as an illness. Obesity was seen as a personal failure. They had either overeaten or been overfed. Someone was to blame for this obesity. No one understood that this was something that we, as parents, have no control over. Across the years, we've been offered and tried weight-loss drugs that didn't work, growth hormones that made them taller but also caused weight gain to match, and we're told that once they were adults, they could have stomach reduction surgery. We joined and paid for gym memberships that went unused because they hated going and nothing is worse than walking on a treadmill next to your crying teenager. We visited many different dieticians and nutritionists whose all advice was to feed them less and to keep a food diary. The underlying reason for their eating was never explored or addressed and none of these offered solutions addressing the true problem in BBS. I know that my girls are going to be blind and blindness is bad, but it's not going to kill them. My daughters had a kidney transplant, and kidney failure is really bad, but there are many options available to treat it and to live well with it. Obesity, however, is a problem. The added strain on their bodies from continuing to gain weight can never lead to anything good. Excessive weight kills people. I hear all the time from other parents that their families are not accepting or supportive of their children with BBS and I know that's true in our life. There's no understanding of what we, as a family, are going through. Family and friends drift away because socializing almost always involves food and food is a trigger in our family. Once people see a melt down, they don't want to come back to see another. Next slide. The void in our lives from families and friends who don't understand the disease doesn't stop us from wanting support and understanding, and this is why our BBS community is so closely knit. One of the greatest pleasures in my life was to be involved in the creation of the BBS Family Association, way back starting in 1997. This is a picture of our BBS community. In the top left with the red shirts we're all gathered in Salt Lake City for a conference. The bottom in the blue shirts we're gathered in Durham, North Carolina for a conference, and my girls are wearing their yellow shirts from the Iowa conference. There are hundreds of us, and we understand each other because we're walking the same path. The vast majority of BBS families I've met across the years have gone through the exact same struggles that we have in both weight gain and lack of services or understanding. When I need support, I first go to my BBS community. What every BBS parent wants for their child is to live a full happy life without the overwhelming, all-encompassing drive to eat and the obesity that results. For this to happen, we need your help. You are truly making a difference in our lives. I thank you, and the entire BBS community thanks you for giving us hope. Thank you.

Thank you, Mary. There's a lot to digest there. So with that, we'll move to Dr. Conroy, who is an investigator in our trials, and she has patients with BBS under her care, and we're very excited that she's joining us today to share her experiences. Dr. Conroy?

So I have to be mad at whoever put me after Mary because that was just such an amazing talk that anything I talk about now is not even going to hold the candle to how great of a job she did. So Mary, thank you for that and for sharing your story. And I will do my best to follow that as best I can. So I am Dr. Conroy. I'm a pediatric endocrinologist and obesity medicine physician. And as you heard earlier, I'm a Medical Director for our pediatric weight management and our pediatric type 2 diabetes program. Myself and one other colleague who's a general pediatrician, the 2 of us are the obesity medicine physicians for our hospital system. And then we have with us dietitians and therapists and nurses to help support our team. We are in the western part of Massachusetts. Our hospital system has about 5 hospitals and then a little over 800 medical practices throughout the community. So they serve about 1,500 physicians between the hospital and the community pediatrician. So in my care, I have -- I'm actively following about 600 patients who have obesity and this ranges from 0 up until about age 21. We tend to send them over to our adult colleagues once they hit 22. And in that group, I'm actively following 4 patients who have Bardet-Biedl syndrome. And of those 4, it's -- so actually, 2 of them are siblings and the other 2 are first cousins. The siblings were diagnosed by a geneticist when their pediatrician noticed that they were having excessive weight gain in early childhood and also had some visual impairment. And the other 2, the cousins were diagnosed by my colleague when each of them separately had gone to see her for the excessive weight gain. She had noted some developmental delays and visual difficulties and had the genetic testing done and that's how they came to the diagnosis. Next slide, please. So a little bit about Bardet-Biedl syndrome or BBS. This is a rare genetic disease of obesity. There are a number of features that are very common in patients who have BBS and Mary's 2 girls actually had -- she named almost all of them. One of the most prevalent ones is this early onset severe obesity. So over half of these children who have BBS were either overweight or had obesity before the age of 2 and over 70% of people with BBS have this early onset obesity. Other features that we see often are the visual impairments, developmental delays or learning difficulties. We've also seen kidney dysfunction, cardiovascular disease, some genital anomalies and then what we call polydactyly, which is having extra digits on your hands and feet, so like an extra finger or toe on your hands and feet is another common feature. The things that I've noticed about in the patients that I follow are they all have the worsening visual function, the learning difficulties and then this early onset severe obesity. Next slide, please. So this is a cross-sectional analysis of data on people who have BBS. And what they wanted to show was the percent of people who had obesity and overweight at different ages. So you can see here, it's divided up by obesity, which is a BMI that's over the -- a Body Mass Index over the 95th percentile for age and gender or overweight, which is a Body Mass Index between the 85th and 95th percentile for age and gender. And so what you can see based on the numbers is that over half of kids with BBS under the age of 2 are already suffering from overweight or obesity. And when you get to these older ages, almost 100% of these kids are struggling with not having a normal weight, with a very large percentage of them struggling with obesity at these very young ages. Next slide, please. So the reason this becomes an issue for us, especially for me as a pediatric endocrinologist and weight management physician is that the childhood obesity is tough to treat, but the comorbidities of childhood obesity are very difficult to treat. So we know that obesity in general, is associated with a high risk of developing comorbidities, diabetes, sleep apnea, hypertension, heart disease, stroke, orthopedic problems and many, many other things. And people with BBS are not immune to any of this, they are all at risk of developing these problems as well. So you can see from this study, which looked at data on people with BBS and looked at their obesity-related comorbidities. And they found that over half of them had metabolic syndrome, which is a combination of abnormal cholesterol, abnormal blood sugar, elevated blood pressures as well as a large waist circumference. 16% had type 2 diabetes, 67% had hypertension and then another 17% had moderate to severe sleep apnea, which generally require some sort of treatment with either CPAP or BiPAP. What I find in my role that's very difficult is that for a lot of these treatments there are plenty of FDA-approved treatments for adults with hypertension, and adults with type 2 diabetes and sleep apnea and things like that. But because it's only been over the last decade or so that we've really seen such an increase in the prevalence of these diseases in kids, we don't have a lot of the same treatment options because they haven't been studied, they haven't been FDA-approved. So when I get these kids who are having a lot of these obesity-related comorbidities, I'm often left with very little to offer them as far as treatment. And the obesity itself can lower their life expectancy. And we're finding that in kids who have obesity and these comorbidities, their life expectancy is even lower. So it's really disturbing and troubling to be able to offer them so little with such serious diseases. Next slide, please. So we know that for BBS, the obesity comes from hyperphagia. Hyperphagia being this intense drive to eat, this preoccupation with food. And we know that, that drive, that preoccupation with food is coming because of the gene defects that we see in patients with BBS as many of the genes that are associated with BBS are involved in the appetite regulatory pathway. So when there is a defect in the gene, there can be a defect in the appetite pathway, which can make somebody no longer feel full, and so they're constantly feeling hungry and constantly wanting to eat and the increase in calories is what leads to the obesity. And because it's genetic, it's starting from birth. So shortly after birth, you're seeing these issues. So some of the key findings for hyperphagia include taking a longer time to feel full while eating. So this is having large portion and a second portion or a third portion before you're finally like, okay, I can feel full. And sometimes feeling full is to the point of having overstuffed yourself where I've had some patients who they've vomited and then they come back to eat more because they've cleared their stomach. This feeling hungry again right after a meal. So Mary actually alluded to this, she had mentioned that her kids will finish breakfast and then wonder what's for lunch. So just as soon as one meal is over, you're already shortly after asking for the next meal because you're hungry again. And then there's this thinking about food constantly, which, again, Mary alluded to with her girls, but food is constantly on the brain. You're constantly hungry, so you're thinking about food. Where am I going to get food? Where is the nearest food? What can I eat later? What can I eat right now? How am I going to get the food? And it's hard to focus on other things. It's hard to focus on school work and your job, and just hanging out with friends because you just can't stop thinking about the food. And then there's food-seeking behavior. So this involves things like sneaking food, stealing food, hoarding food, hiding food, eating food off other people's plate to the point that just like Mary has to do for her family kitchen, people have had to lock cabinets, lock refrigerators. I have one mom who put cameras in the kitchen and is up past the night just watching the camera so that she can see if her child is going into the kitchen so she can go in and get him and take him back out. Other things that I've heard from my families include notes coming back from the teachers saying, can you please pack more lunch for your child because they're eating their lunch and then they're complaining of hunger for the rest of the day. I've had some who have found it difficult to go to restaurants because of the stress, of the worrying about the food being accessible and tantrums and things, and that's been really troubling as well. Next slide, please. So the hyperphagia issue, like I said, because this is coming from a genetic component, it starts early shortly after birth. And as we had mentioned before, over half of these kids under the age of 2 have developed overweight and obesity. And we're finding that over 90% of caregivers are reporting this increase in interest in food and hunger in their kids before the age of 5. As we mentioned, the hyperphagia does have an early onset. And we have seen that compared to patients who have general what we call polygenic obesity, the patients who have BBS have a much higher degree of hyperphagia -- score much higher on hyperphagia hunger scores than people who have non-syndromic obesity. Next slide, please. So how do we assess for this? Unfortunately, there's no gold standard for how we can check for this. So there's no research-validated questionnaire that's been replicated and used on multiple patients with BBS or really any other genetic obesity syndrome. And so for that reason, most of us who are seeing patients with this, we've kind of come up with our own set of questions. And a lot of them are taken from other as yet unvalidated hyperphagia questionnaire. And then some questions are formulated by things we've learned from our patients and their parents, so they are questions that we can then ask future patients and parents. So the hyperphagia questionnaire that has been available for patients with Prader-Willi syndrome and has been used for other obesity syndrome, breaks down hyperphagia into 3 different types of behaviors. There is the hyperphagic behavior, which is the food-seeking behavior. So the sneaking, stealing, hoarding, hiding. There's the drive, which is the preoccupation with food, the constantly thinking about food, having trouble focusing on other things, constantly talking about food. And then the severity, which is what happens when they're told no. So that's the tantrums and the fights, and the screaming and the crying that can occur because they're told they cannot have more food. Some of the questions I've found very helpful for my -- to ask my patients are, what things were like in infancy. So if they were breastfed and the pediatrician said, if your child is breastfed, they should be getting fed about every 2 hours. Are you -- do you remember that your child needed to get fed more frequently than that? Or if they were getting formula-fed and the pediatrician said, you should expect them to be getting fed every 3 or 4 hours. Did you find that, again, your child needed to get fed every 1 or 2 hours, and you just felt like they were constantly crying for food? In toddlerhood I asked about issues with grabbing food off of people's plates with screaming and crying if they're told no, that they can't have more food. We're trying to get into the garbage and eat food or trying to get into the cabinets to get food, trying to grab food from other people if they see it, whether it's people they know or strangers. Some of my older kids, I also again asked about the severity. So what happens when they're told no. I have some patients who have -- who cry. I have some patients who scream, some will start to hurt their parents like go and hit them, throw things at them, some start to hurt themselves. So these behaviors can be really, really distressing for the family when this is what happens when they're denied food. For some of the older kids and ones who may not be as developmentally delayed as others, I will ask them about that preoccupation with food. So I asked them how is it at school? Do they have trouble focusing on their school work because they're thinking about food? Is it hard to go out with friends because you keep thinking about food? But how far does this preoccupation take them? And I'll also ask them about their eating habits, when they eat, do they feel hungry 0.5 an hour less, 0.5 an hour later? Do they feel like they need to eat more to feel full? Is this causing them some embarrassment or concern? So I will try to address those behaviors in those older kids that are able to answer the questions. Next slide, please. So my experience, I have had the benefit of having 2 patients who were able to use the setmelanotide. One patient has BBS and was using the medication through a clinical trial through Rhythm. And the other patient was able to get commercial product because she had one of -- she has one of the genetic obesity enzyme defects that is already FDA-approved for medication. So I thought I would just tell you a bit about both of them and how they fared on the medication, just so you can get kind of a full picture. So for the patient with BBS, she's a young adult, I guess now, she's about 19. And for her, the issue with the medication that she felt was the most helpful was that she finally felt full. She was able to leave food on her plate, which she was never able to do before. And that was something that mom had noticed and that she had noticed and they were really, really excited about that. She also felt like she could actually do other things because her life wasn't so fixated on food and how to avoid eating too much or not think about food or where she was focusing on the food aspect of going to the movies, now she could go to the movies and enjoy the movie, which was something very new for her too. She had -- she's been having successful weight loss and she's been very happy with that. She does the -- right now because she initially had been doing the injections herself, but her vision has deteriorated. So now her mother is helping her with the injections. And her biggest side effect from it was having some bruising at the site that would then kind of fade away. So she might have a little brews and then after about a week, it would be gone. And she did also have some skin tanning, which she was totally happy about, because for her, it just -- it made her look like she was in the Bahamas and just came back with a nice tan. So she was very happy with the tan. And she actually said she had no problem with the bruising. She was like even if the bruising stayed a while, I'm losing weight, I can focus on other parts of my life, this is totally worth it for me, and so she's been really happy with it. The other patient is younger. She is now 13, and as I mentioned, she is on commercial product. And she has had a great success with it, too, in a different way. So I have been following her -- I've been at Baystate for 11 years. So I've been following her for like 10 of those years. And she will come in with perpetual weight gain, about like a pound a week of weight gain. And even though she is a growing child, she was still gaining much more than she was growing. And so her weight per height was just soaring exponentially and that we just felt like there was nothing we can do. The medication has allowed her to not feel hungry as often. So she's able to adhere to the diet changes that our dietitian has talked to her mom about, and she's actually -- she hasn't been gaining. So despite the fact that she hasn't lost like my young adult patient has, the fact that she can come in for a visit and instead of having gained 12 pounds in 12 weeks had not gained anything, that was the first time we had seen that happen in the 10 years that I've been treating her. So for us, that was a huge win, and we are so thrilled with it. She has not been having the side effects of the bruising or the skin tanning and she has been tolerating the injections well. So I'm hopeful that she'll continue on the medication and continue to grow and have her BMI decrease. As a community, am I talking too much? Is this...

Great. You're good.

Okay. This is something I'm so passionate about. So I feel like I could keep you all here for a really unnecessarily long amount of time. So I just wanted to make sure we're okay on time. As a weight management physician, it's really frustrating to not have a lot to offer my patients. And I struggle with it a lot, right? Like even for my patients with general polygenic obesity who cannot seem to get their BMIs down with lifestyle modification, until they hit 12, I can't offer them medications or anything more than just keep working on your diet, and that can be -- that's very frustrating for me. And so I know it's very frustrating for my families as well. And in cases like this with patients with BBS, where the weight gain is from this genetic defect that's causing this intense drive to eat, this intense appetite, it's even more frustrating because we know that run-of-the-mill dietary modification, increase your exercise, like it is not going to work. And we worry that with them developing obesity and consequences of their obesity at these young ages can really cause them a lot of problems, not only with the obesity-related comorbidities but with the other things that they are at risk of developing like the kidney issues that Mary had mentioned one of her girls was suffering from. So to have a medication out there that could actually help them is this amazing miracle that showed up and could have such -- could make such a dent in these people's lives to help get their weight under control, which could lower their risk of developing a whole slew of other problems. I know I said I have 4 patients right now who have BBS. And once this medication is FDA-approved for BBS, I will definitely be reaching out to them to let them know that it's here and see if they would be interested in starting treatment. But I also think that my colleagues, the community pediatricians, my colleagues in genetics, I think there's -- they all see other patients who have BBS, to my colleagues in nephrology and in renal that will then hear about this medication and come and say, I've been talking to my BBS community, I heard this medication is there. How can I get it? Let me be a part of this. And then I will be here to give it to them and monitor them, and help them through this journey. So I think my hope is that it gets approved, and I just get inundated with patients who are lining up to get this medication and then I can be the one to prescribe it, monitor and then see them through this amazing course of successful weight loss and reduction in all of these comorbidities. Okay. And now I will stop.

Thank you, Dr. Conroy. That's great. So now it's my pleasure to turn it over to Dr. Bob Haws, and like Dr. Conroy, Bob is an investigator in our trials and has been a valued partner in our clinical development since we enrolled our first patients with BBS in our exploratory Phase II basket study more than 6 years ago. So Bob, over to you. Hopefully, Bob is still on the line there.

Bob, are you on mute?

I am. Can you hear me now?

We can. Perfect.

Thank you so much. I apologize. Dr. Conroy, that was a great presentation, and Mary, as always, thank you very much for inspiring what we're doing. I'm a children's kidney specialist with a long-term interest in Bardet-Biedl syndrome. I had the opportunity of taking care of Ashley 28-plus years ago. And from that, became very impressed by the BBS community and the opportunity to make a difference. We developed a Center of Excellence for Bardet-Biedl syndrome at the Marshfield Clinic, which is a multi-disciplinary program where individuals come for 3 to 4 days to receive comprehensive care. We also developed the clinical registry investigating Bardet-Biedl syndrome, which is a registry that tracks about 700 individuals across the world with BBS, looking at features of the disease and it's given me the opportunity to hear what is the big challenge we face. And almost every time it's hyperphagia and obesity. What can I do for this? Whether it be the individual with it or the parent of a child with Bardet-Biedl syndrome, who says, I don't know what to do. What can I do to make a difference? Years ago, I started to do a behavioral therapy study to see if we can make a difference in obesity with BBS through that. And then followed by that, I approached another drug company about using GLP-1 agonist to see if that would be effective in BBS. That's never got off the ground, because I was approached in 2016 by Rhythm Pharmaceuticals and informed about setmelanotide. It really caught my attention because unlike any other therapy, it targeted the real problem of obesity in this disease. And so with that, we moved forward with the initial -- the clinical trials of setmelanotide. I'd like to share today with you a little bit about the Phase III clinical trials. So next slide, please. In this slide, you see a diagram of the design of the study, which was a double-blind study, where individuals initially were either on placebo or active drug. There is an open-label treatment for all patients in a study that was conducted about 52 weeks. Now this is a really important study because this was the largest and the longest Phase III study ever conducted in Bardet-Biedl syndrome and Alstrom syndrome. It's really novel because it gives us opportunity to find a therapy that might work, and I'm really convinced it's doing very well. Now the focus was on -- specifically on the -- looking at the drug itself, we didn't do any specific guidance on a diet or exercise. Of course, when they come to clinic, we always encourage those aspects of care. But the drug was -- the study was designed to look at setmelanotide. So if we go on to the next slide, please. In this study, we enrolled 32 individuals, 26 individuals completed the study. The average age of participants was about 20 years of age with a range between 7 and 44 years. About half were less than 6 -- half of them were less than 18, the other half were above 18. The individuals were obese. As you can see down towards the bottom, the average weight was 112.3 kilograms, which is roughly 250 pounds. Now please remember, these are individuals between 7 and 44 years of age that were in the study. For children less than 18 years of age we use the BMI Z score, which is a way to look at the number of the -- weight compared to the normal and the mean Z score was 3.7, which is almost 4x the norm or [ 4 divisions ] above the norm for these individuals. So obesity was very much a common feature for those individuals participating in the study. Next slide, please. Now the remarkable slides here, many of you have seen, but I want to emphasize was what we've identified during the study. In those individuals, 18 years of age or older, we saw that their baseline weight was 128.4 pounds or about 283 pounds. I said 128.4 pounds, I meant 128.4 kilograms or about 283 pounds at the beginning of the study. And you can see that over that year's span, a remarkable decrease in weight with a mean change in weight of 9.5%. Now as Mary emphasized and Dr. Conroy reinforced, weight loss is exceptionally uncommon in this syndrome. This week, I spoke with the family. They've come to our clinic. After the clinic, their son who is 26 years of age, lost 30 pounds. He did a really good job of try and control his weight, but the weight quickly came back with his own efforts to lose the weight. So that's a typical pattern of individual with Bardet-Biedl syndrome, long-term success is not commonly achieved. In this study, we see long-term success, which is really remarkable. Could we go to the next slide, please. So we found that in this study at the end of that 1 year, is 60% of the individuals achieved at least a 5% weight loss and almost 50% achieved a 10% weight loss. Again, remarkable results in this study with setmelanotide in individuals between 7 and 44 years of age. Next slide, please. Now I want to turn to children. And as a pediatric nephrologist, this is very important because I want to be able to see these children lose weight because it's critical for their health. And we looked at BMI Z score, again that's looking at the number of standard deviations above the norm, and we looked at disease score of these children over the 52-week study period. Now I sometimes hear advertisements about people losing 40, 50 pounds in a week and how successful it is. I don't know that's always healthy. In this population, we see a gradual, steady weight loss in the patients over the 52 weeks. We see the disease score that started at 3.7 drop down to 3 by the end of that 52-week study, again, remarkable improvement in their patients' weight during this critical period of time where weight gain is so often accumulated. Next slide, please. So when we looked at the Z score of these individuals who really achieved a meaningful Z score. So 86% achieved a 0.2 or greater decline in their Z score, 71.4% greater than 0.3. That's pretty remarkable because, again, we don't see a weight loss in Bardet-Biedl syndrome. We only see weight gain. And to see the subtle weight change in children is really changing the future for each of these children, their lives. Next slide, please. Now the slides I've shown up to you here before have been presented in a number of different meetings. What I'll be presenting to you today has not been presented. It will be presented in a meeting in June. And if we look at the what we call the open-label extension trial, where we have individuals come into clinic every 3 months for a follow-up visit to see how they do over the period of time that they continue on drug. This is an extremely important study to me because the question is, do they keep losing weight? Or do they have a phase where they just start gaining the weight once again? So if I can have the next slide. In this study, we saw success. The 24-month efficacy data is provided for you here. On the left-hand side, we see that there's a minus 14% -- 14.3% change in the body mass index in 19 individuals. Remarkable. Remember, this is over 2 years. In the middle slide, we look at the individuals -- in the middle of the slide, you see individuals 18 years of age and older, and you see that they had a minus 14.9% change in their body weight. In children, their Z score went down by, on average, 0.72. This is wonderful to see this type of weight loss in these individuals. Now you might also ask yourself, well, was it safe? Do we see more side effects as they continue on the trial? And as an investigator that took care of a number of the participants, I was so impressed that there really were not any significant changes in the safety profile of these individuals. One person did discontinue, but it was due to adverse event unrelated to setmelanotide. Could we go to the next slide, please? Now we've talked a lot about weight loss, and that's critically -- that's -- as a person that likes numbers, that is very important. But I also want to know about what it does to hunger because if the drug is going to be effective, we want to change that hunger. And both Mary and Dr. Conroy talked about how hunger is such a challenge for Bardet-Biedl syndrome. And here, you see in this, the individuals in the dark blue are individuals who are in active drug, individuals in the gray are in the placebo. During the first 14 weeks of study, you can see a dramatic difference between the hunger score of those on the placebo versus those on active drug. After 14 weeks, there is a reduction in the dose for individuals in active drug, while the other individuals who now were entering the treatment phase were also started on drug. So they're on 1 milligram and that has increased up to 3 milligrams. You can see how their appetite or the hunger score went up in those who had been treated on active drug and came down nicely on individuals who were on placebo and now they're in active drug. And that suppression of appetite continued throughout the entire 64 weeks of observation. So we see a wonderful decline in their appetite or their hunger scores during this period of time. I also just want to make a comment here that I don't think that we always recognize how hunger affects these individuals. One of our individuals who started on the clinical trial, who did it, he said to me, I'm joining this trial not because I'm hungry, because I want to make a difference for the world. And I want to make a difference with the BBS community. He weighed about 350 pounds at the time that he entered the trial. After the first dose of setmelanotide, I received a call from his mother, who said they had gone to the airport to catch their flight home, and this young man ate only a half a sandwich. They said they've never seen this ever before in their life. And he said, I understand now what hunger really was. Before this time, I never understood really the word being full. Can we go to the next slide, please. In this, as we looked at the hunger score, 57.1% of the individuals over 12 years of age achieved at least a 25% reduction in their hunger score. On the right-hand side, you see there's a greater than a 1-point improvement in their hunger score in 71.4%, and greater than 2-point improvement in hunger score in nearly 43% of the individuals. Next slide. Now pharmacological therapy is wonderful. But if it causes too many adverse effects, it's hard to continue that drug. But in this case, we found really excellent tolerance of it. So there were treatment-related adverse effects in essentially everyone, but that was the most common side effect was increased pigmentation of the skin. And as Dr. Conroy had mentioned, some individuals really enjoyed having a little bit more of a sun tan after being on the drug. So for the other people it was disconcerting, but hyperpigmentation was seen in the majority of the individuals. Nausea was described. I had quite a few individuals in this clinical trial, and I have to admit that I did not hear about nausea from any of the patients. If it was present, it usually is less than 1 or 2 days before it resolved completely. There is, of course, injection site irritation, redness sometime is observed. But this was really quite mild and oftentimes resolved itself over time. So the drug is remarkably safe and remarkably effective in treating both the hyperphagia and obesity of Bardet-Biedl syndrome. Next slide. So what are my conclusions. First of all, I am very pleased with the opportunity I've had to participate in this clinical trial. I know that obesity and hyperphagia in BBS are serious and severe. As a nephrologist, I see that the obesity keeps individuals from getting kidney transplant, so they're destined to life on dialysis alone. It's clean -- this drug, this therapy has had clinically meaningful impact on weight loss and hunger reduction. It's remarkable and patients report an improved quality of life. And I've seriously heard that from every individual who's been on this clinical trial that it has improved their quality of life, it's improved their ability to focus and do better in school and in life. And then finally, the community is anxiously waiting for setmelanotide's approval. I get calls, e-mails on a regular basis almost every single day from people asking when it will be on the market. I want to be on setmelanotide. They're anxiously awaiting for this. So those are my conclusions. It's a privilege to talk with you today, and I hope I've answered some of your questions that you might have about this very effective therapy.

So Bob, thank you very much. And again, I think we got a good start on the questions. I have a number that have come through. And so I think at this point, we'll go to the Q&A section. And so we have Mary, Dr. Conroy and Dr. Haws who are available, and I'll start with some of the questions that have come through. And I think a big part of the focus here is trying to understand who are the patients for whom setmelanotide/IMCIVREE would be indicative or most appropriate for and how might it be used? But let me start with a very specific question here. And you've heard, I think, from all 3 speakers about the early onset of obesity and the associated comorbidities. And the question is, what do you think long-term implications are for patients who are able to start setmelanotide early and can it stay off obesity if started early enough? And so we know our current label is indicated for 6 and above. We're doing a trial in patients, as Bob and Dr. Conroy know, in patients who are 2 and above. But ideally, with a genetic disease, you might want to intervene early, but what's your opinion, and I'll start with Dr. Haws and then go to Dr. Conroy just in terms of the value of early intervention.

I think that's such a great question. It's critical. I do believe that habits of eating behavior begin early on in life. As Dr. Conroy pointed out, these are happening in babies and going on into young childhood. And so if we can make a difference in their obesity when they're 2 and 3 years of age, I think we have the best chance of making a difference. I think when we -- it's a wonderful drug for people that are 30, 40, 50 years of age, but I think its best opportunity is in children less than 6 years of age. I'm delighted that Rhythm is pursuing that study in looking for individuals treated with less than 6 years of age. We enrolled our first patient today. There's 5 years of age, who will be starting on IMCIVREE. I think it's the good -- it's the smartest idea it could be to start it when the child is 2, 3, 4 years of age.

Dr. Conroy, I don't know if you have anything to add. I mean you spoke extensively about the comorbidities and the importance there. And so any additional thoughts?

I totally agree with Dr. Haws. And I think that starting the medication to almost in a way of like preventing further excessive weight gain will allow that child to grow and gain weight in a more appropriate manner. It's a lot harder. So I keep going back to Mary's slide with the growth curves in it, right? And she mentioned -- I can't remember if it was Carly or Ashley, but somebody was 45 pounds at the age of 3. Trying to now let that person grow into the 45 pounds, you're talking about 2 or 3 years of maintaining weight and growing into that. And that's a long time of really struggling to try to keep the weight stable. So starting a medication as early back as you can so that they can just kind of grow in this -- in a more like healthy, slow and steady way will really lower their risk of getting these problems later, and then lower -- and also make it easier for them then trying to lose excessive amount of weight as opposed to just slowing down that gain.

Great. So again, for the 2 of you, a follow-on in a sense. Can you give us some sense of the magnitude of impairment in hyperphagia weight loss that patient would need to achieve for you to keep them on therapy? In other words, what would you see as a clinically meaningful response that you would characterize as like any drug, we make an assessment, is it worth? There's always a cost, whether it's a side effect or just the financial cost of keeping them on therapy. So what is sufficiently meaningful?

Dr. Conroy, do you want to go first? And then I'll give my opinion.

Sure. So for me, kind of like I mentioned with that second patient of mine who was on the commercial product. With my experience with patients with BBS is that they're constantly gaining. So a clinically meaningful result would be if my patient came in and had no weight gain. That for me is very meaningful, especially if they're a young child and still growing because that will certainly make their BMI decrease. I know from a -- like a study standpoint, it might not look as exciting as someone who's lost 20% of their body weight, but that's not something that is realistic for these patients because of that struggle with hyperphagia. So for me, my bar is set pretty low, but I know some of my other colleagues who also treat patients with BBS kind of feel the same way that no weight gain is actually significant for us and weight loss is that much better.

Dr. Haws?

So I have been so impressed over the 6 years I've been using setmelanotide, and as I see the impact on people's lives is sometimes hard to quantify as an effect on the Body Mass Index or so. And so if I can give just a few examples of that. We have one young lady who is on the medication and I never expected this, but we do neuropsychological testing in a lot of our patients. And after she's on the medication for a period of time, her cognitive function, her IQ went up by 18 points. As I talked with the neuropsychologist, that person, that neuropsychologist didn't think that that's something we have sprouted new and better brain cells, but rather we had helped them be able to focus on things better. How do you quantify that? It's making a huge difference. We have individuals who, for the first time, can go out to dinner and not have someone stealing food off their plate because their child is so hungry that they want everything that they can get a hold of. Those are hard to quantify. Now I understand that insurance companies and so on like to have something they can quantify. But you see in what I reported that the vast majority of individuals lost at least 5% of their body weight, and we had significant reductions in their hyperphagia scores. And this is a lifelong benefit to these patients. And so, to me, I want to see the drug used in individuals as long as they're feeling better. And that's a very subjective thing. As long as they're feeling better, I like to see them stay on the drug, very few -- besides skin darkening, very few adverse effects.

And following up, so Mary's story is powerful. I mean, again, you can't listen to the story of Carly and Ashley without having sort of a profound sense of wow, what an incredible burden carried by both Carly and Ashley, and of course, the family as a whole. How representative do you think that story is? I mean Bob, you see a very large number of Bardet-Biedl patients. And is that a typical story? Or do you think Mary's story a bit unusual?

Mary's story is the story of Bardet-Biedl syndrome. It is the story of Bardet-Biedl syndrome. Individuals have severe obesity. The paper by Palmer shows that in childhood, the vast majority, 90-plus percent have obesity or at least overweight that is changing their lives for the worst. The story that Mary gave, I've heard over and over and over again, Mary was articulate and gave a wonderful rendition of the story of her experience, I have heard the same thing from almost every parent that I meet in the Center of Excellence.

With that, let's go to Mary. And Mary, maybe you mentioned how important the Bardet-Biedl community was to you. And maybe you could say a little bit more about how tight that community is? And what do you look for in that community in terms of support? Or what's the nature of your interactions there in terms of living with this disease?

So our relationship in the community is we consider each other family. We go to each other. We go to the community when we need our family because a lot of times, our families don't understand what we're going through. They don't understand that drive to eat and they think we should just not feed them so much and it would be better. But we know we can talk to each other. We have several different Facebook pages that go on. There are other Zoom meetings that are held twice a month on one of the Facebook pages where the mothers and fathers can just get together and talk. We also have people with BBS supporting each other online as well. It's so important. When Ashley was diagnosed with BBS, we were told all of these things that she was going to be, and then we were told that there was nobody else, that we were it. And that's what kind of led to the formation of the foundation of looking for people that had BBS and joining together so that nobody else had to go through that alone and be told that all these bad things are going to happen, and now go home with it. So we have people that reach out to us on our Facebook pages, sometimes before they even have their genetic report back because they're sure that their child has BBS. So we're really thankful for that, that we can provide that for families so that they're not alone. And we do walk together on this and whether to cheer each other on and listen and have a springboard, people can vent and they don't get judged because we all know, we've all been there.

So maybe following up having Bardet-Biedl syndrome with all the different problems. I mean you highlighted the vision loss and the kidney challenges, Ashley's challenges. Why wouldn't a family or patients specifically want to use a treatment such as setmelanotide if it were available? And I'm asking that question because maybe with all the other manifestations of the disease, it's just -- it's overwhelming and a treatment for one part of that just is too much. It's not something they might seek.

I don't think that there's any family who would turn it down. Like Dr. Haws said, I have people e-mail me or message me on Facebook almost every day asking me, when is it going to be available? We all want to be on it and from other countries as well. I can't imagine anybody saying no to it. I think for the -- maybe for some of the older people with BBS who've already lived a long life with BBS, they may say that it's an unnecessary treatment when they're in their 50s or 60s. But I can't think of any family that would turn it down, I can't think of anyone.

And Dr. Haws and Dr. Conroy, this question, I think, dovetails with that a bit. So what is the profile of your BBS patients most likely to benefit? And Mary highlighted one segment of the population who might not seek therapy in the same way. But the specific question is what proportion of your patients would you prescribe the therapy for? So may I start with you, Dr. Conroy?

So I will offer it to everybody. I think for the person who is still struggling with their weight, I will offer it, for the person who has been able to maintain their weight, but it takes 200% effort and focusing on their diet and food has become their full-time job, I will offer it to them so that they can get some part of their life back. So I will offer it to everybody. I think just to talk a little bit about what you had asked Mary before. I think one of the reasons that people will want this is because the kidney disease, you deal with, the heart issues, if you have them, the visual impairment, there are things that you deal with like in a broad sense. But that hunger, it's constantly in your head. It's always there. It's constantly going off in your mind, the thinking about food. So to be able to just get that to stop so that you can focus your attention on other things. I think that's why people will jump on it. The only other small group of people I can think of that might be hesitant to do it would be the person who says, okay, well, the medication hasn't been out long enough, I'm worried about what happens a year from now or 2 years from now, will the medication be as effective or will other problems come up? And that's something that I totally respect for someone to have as those concerns. My point back would be, but what happens if they're now 1 year later, they're 50 pounds heavier, and now they're struggling with type 2 diabetes and severe sleep apnea, and you can't get them to wear their CPAP and now they're going into heart failure. So what about that part, too? So I would still say there's an argument for that as well. But sorry, to answer your original question, I will offer this to everybody and anybody who wants it, I will prescribe it, and then fight for them to get it, whatever needs to be done, I will fight for them.

Okay. And Dr. Haws, same question.

Yes. So the -- there are people that come to our clinic who -- the vast majority are overweight or obese as shown in the data, 90-plus percent. There are some individuals who are not overweight, they're rare. I have a picture of a group that we had one evening, we have an evening get together before COVID anyway. And there is about 10 kids in there in the picture with me. And one is quite a thin child sitting next to his sister who is quite obese. They both have Bardet-Biedl syndrome. For reasons I don't understand, he decided to suffer from hyperphagia and obesity. So there's going to be rare atypical patients who I'm not going to treat. But the majority of patients just like Dr. Conroy, I want to invite them to receive the therapy. There might be a few people who have needle phobia, we tried to overcome that and so on. But the vast majority are so anxious. I can't say a number to it, 90%, 80% of our people are very anxiously awaiting the arrival of setmelanotide in the market. And so I would say that I'd prescribe it to the vast majority of my patients with exceptions of individuals who are atypical Bardet-Biedl syndrome patients.

I was wondering, can I add something?

Mary, please.

When I think back to when Carly was little, she was a very difficult child and she cried all the time and had tantrums all the time and was hungry all the time, and she also had silly activities we didn't know. And this would have made our life so much easier if we didn't have to go through this. And I know there's a lot of families who are that age between 0 and 7, it's really hard for parents because you don't know what's the matter. This would have stopped all of that, and it would have been a blessing to have at that time. She was a tough baby.

Well, Mary, I think that's a good answer to close on here. So we'll wrap the Q&A section, and now move to an update on where we are in terms of commercial readiness. So my thanks, again. Mary, thanks so much for sharing your story. It's really powerful. And thanks to Bob and Rushika helping us better understand this disease and the data that we have so far. So with that, I'm going to turn it over to Jennifer, who's going to take us through where Rhythm is today.

Thank you, David. And I really also want to thank our speakers for their presentations today. As you heard from Mary as well as Dr. Conroy, there is a significant impact of the hyperphagia on the life of patients. And I can say even personally since joining Rhythm, just hearing the consistency of how it's been explained by the HCPs as well as the patients and caregivers have really even solidified that impact for me. We also outlined that there remains a need for additional therapeutic options to address the hyperphagia in addition to the early onset severe obesity and associated comorbidities. Dr. Haws also spoke to the mechanism of setmelanotide addressing the root cause of these manifestations in patients with BBS. He spoke to the efficacy of setmelanotide on hunger reduction and weight loss and outlined its consistent safety profile. What I now want to walk you through is how we have been preparing for a next potential approval in BBS. As a reminder, IMCIVREE has been commercially available since November of 2020. Since its initial approval, we have put in place a team who have been actively preparing for the projected March 16 PDUFA date. Next slide. For the approval of IMCIVREE for patients with POMC, PCSK1 and LEPR mutations, we had limited field resources deployed. When we discuss what success would actually look like, we outlined this would include: one, HCPs and patients recognizing the need for IMCIVREE; two, success in attaining reimbursement for IMCIVREE; and three, because of the benefit experienced on drug, we had patients who remained on IMCIVREE. I'm really proud to say that we have successfully achieved all of these objectives within the first year of launch. And we have leveraged the learnings to be able to supplement our planning for the next potential BBS launch. Next slide. One key learning was the importance of a high-touch patient service organization. Through the interactions of our team with patients, we have heard how IMCIVREE has made an impact on their lives. Two anecdotes captured here, starting with the one on the left. A mom of a 15-year-old girl had outlined that her daughter has always been extremely active in sports. She had tried diet, lifestyle changes and nothing worked to reduce her weight. Since being on IMCIVREE, she's lost 45 pounds and reports that she feels fantastic. Separately, a 40-year-old woman who has lost 25 pounds, expressed improvements in her mood and energy levels and she has also gotten a personal trainer and express that she is loving it. Next slide. As we now move on to BBS preparations, we have hired a highly experienced and engaged team. The members of the leadership team that you see here have each worked on numerous products and rare disease launches. In fact, several of us have a history of working together on many of these rare disease products in the past. What we know is, although there are some similarities of rare disease launches, there are also distinct differences which impact how we prepare and execute. I will speak to some of our preparations for launch, starting with payer engagement. Next slide, please. So market access is critical for any drug, but it was especially important for us to really understand the perception of IMCIVREE versus other agents within the weight management space. We conducted ad boards and primary market research with payers to assess their perception of BBS and its burden of disease, to evaluate IMCIVREE's product profile and to also understand its anticipated coverage in BBS patients. Next slide. What we learned is similar to other rare diseases, there remains an opportunity for us to educate payers on BBS. However, once hearing our presentation, receptivity to our value story for IMCIVREE in patients with BBS was strong. Payers understood the burden of hyperphagia on the lives of patients, which really differentiated our patient population from general obesity. They also understood that due to the genetic nature of the disease, it caused early onset obesity also in the pediatric population. Overall, IMCIVREE was viewed positively from both a safety and efficacy perspective. Next slide. Because of the understanding of IMCIVREE's value story, payers who are currently covering IMCIVREE for POMC, PCSK1 and LEPR patients would similarly cover patients with BBS upon approval. For those who are not covering IMCIVREE, there was a clear path articulated by appeals to gain coverage. Regarding coverage, similar to other rare diseases and products in that space, what we experienced also in our initial approval in POMC, PCSK1 and LEPR, we do expect requirements for a prior authorization in BBS patients as well. Also similar to our initial approval, we do not expect any therapeutics to access drug. To continue the dialogue, we currently have our corporate accounts team on ground, engaging with payers, educating on BBS and the upcoming potential approval. Next slide. Moving on to our patient support team. For initial approval, the focus was primarily on supporting the reimbursement of IMCIVREE. We know though, through our prior experiences in other rare diseases, the importance of the connection of our patient support team with patients and caregivers. So we have supplemented our existing services with patient educators and educational programs. These efforts focus on disease and eventually treatment education as well as ongoing support from product initiation to adherence while also supporting the support network for patients. Next slide. Now what I have provided some background on is on our access and patient support efforts. But we also know it is critical to help HCPs and patients even get to an accurate diagnosis and to also provide education on available treatment options once IMCIVREE is approved. I outlined upfront that there are similarities of rare disease launches, but also distinct differences and opportunities. The distinct opportunities within BBS to identify and get patients to an accurate diagnosis has led to very targeted efforts of our sales and marketing teams and have yielded positive results. To date, we have already independently identified and are actively engaging with HCPs with greater than 350 diagnosed patients with BBS under their care, and we have just begun. We know there are additional diagnosed patients to be found simply because there are approximately 500 patients in the U.S. that are part of the group's registry. Also, 80% of the patients in the registry are less than 18 years of age. Hence, there are more diagnosed patients, especially adults to be found that are not yet visible to us at Rhythm. In addition, there remains opportunity to expedite giving patients to an accurate BBS diagnosis. Next slide. In summary, I feel very positive about the success achieved following the initial approval of POMC, PCSK1, LEPR patients. And in preparation for the potential BBS launch, we have put in place an experienced, motivated, cross-functional team that is already interfacing with our customers. Patients are benefiting from interactions with our patient support team and programs. Payers understand IMCIVREE's value story and the need in patients with BBS. And we are already seeing positive results as outlined by greater than 350 identified patients through the efforts of our field teams. Let me now turn it over to Sarah Ryan, Head of Sales and Marketing for IMCIVREE, to provide more details around the efforts of her team.

Great. Thank you, Jennifer. So what I will do now is walk you through some of our market research, how that has informed our launch strategies as well as more details around the road map to patient education and execution on delivering IMCIVREE to patients. In addition to the patients -- excuse me, in addition to the payer research that Jennifer outlined, we conducted double-blind, qualitative and quantitative research with 57 physicians who were familiar with BBS as well as with 20 patients and caregivers. Our objectives with the physician research were to gain insights on their understanding of the MC4 pathway, hyperphagia and obesity as well as their reaction to the IMCIVREE profile. With patients and caregivers, we wanted to understand their experiences with hyperphagia and obesity and their impressions of IMCIVREE. So now I'm going to walk you through the findings. Next slide. So let's start with the disease. For physicians, obesity is a significant concern. They recognize there are challenges with current options for management for patients with BBS. There is a need for more appreciation of the impact of hyperphagia on patients and families, and they're looking for a solution that targets the root cause of the obesity and hyperphagia in patients with BBS. Patients and caregivers viewed both obesity and hyperphagia as having significant impact on our overall health. Patients, in contrast to the physicians, have a deep appreciation of the hyperphagia and the serious impact on their quality of life, as we heard from Mary, and Dr. Conroy as well as Dr. Haws earlier. And patients and families are searching for a treatment that can help. Next slide. We also asked physicians, patients of their impressions of IMCIVREE. Perceptions were positive across the board. With physicians, the vast majority would prescribe IMCIVREE as first-line treatment for patients with BBS driven by a targeted nature of the drug, the efficacy and weight loss and the ability to use in a pediatric population. Not unexpectedly, the physicians didn't fully realize the impact of the hyperphagia on the quality of life. Because of that, there was a need to increase the appreciation on that hunger data or of that hunger data. Perceptions of IMCIVREE were widely positive with respect to safety, efficacy and dosing. Patients and caregivers had positive reactions to both efficacy and safety of IMCIVREE only be proactive, as we heard earlier, asking their doctor about IMCIVREE versus waiting for their doctor to initiate a discussion. And not surprisingly, patients were very impressed with the hyperphagia data because they are the ones that are living this day in and day out as we heard earlier, especially from Mary. Next slide. So these insights informed our launch strategies of, one, solidify the need to treat MC4R driven hyperphagia and obesity; two, establish IMCIVREE as the only treatment for these patients; three, ensure a positive experience of Rhythm and IMCIVREE for patients with physicians. And while we're focused at launch on patients who have been diagnosed, there remains a large pool of patients who I'll talk about in a few minutes, who are diagnosed and lost in the system as well as patients who are undiagnosed. Therefore, we need to continue to accelerate diagnosis and help patients find answers. Next slide. So earlier, Jennifer outlined our road map for identifying patients with BBS. And now I'm going to walk you through the key activities that are aligned with each of those segments. As I mentioned on the last slide, there is a large pool of undiagnosed patients or diagnosed patients who are lost in the system. So how are we going to find these patients? For the pool of undiagnosed patients, we're using symptom-based algorithms and machine learning to identify patients who have a higher probability of having BBS and are currently undiagnosed. And in an even more targeted way, we can find diagnosed patients lost in the system by applying the algorithm to a group of patients coded with an ICD-10 code for syndromic disease, which BBS is categorized within. The territory manager team is doing outreach to these physicians in a very targeted, specialty-based approach. And marketing -- and the marketing team is supplementing these efforts with significant nonpersonal digital efforts. Next slide. Another group of patients who have a potential diagnosis of BBS are ones who could be found through the Uncovering Rare Obesity or URO program. And this is Rhythm's sponsored genetic testing panel that test for variants in BBS genes as well as genes tied to obesity. So these can be patients for whom a physician suspected BBS and then has submitted a test or those patients whose severe early onset obesity and hyperphagia was the reason to submit the test, and BBS happened to be the result. We have a field team called the Area Development Managers or ADMs, who are focused on increasing genetic testing with URO through education. And as that ADM team drives testing, the territory managers follow up on the BBS biallelic -- biallelic result, excuse me, and educate the physician on signs and symptoms of BBS. Next slide. So as Jennifer noted earlier, there are north of 350 patients identified who have been diagnosed with BBS. And these have been validated by the Rhythm field team and the physicians caring for them are in our CRM and these are the focus of the territory manager team. Next slide. So what do we know about these physicians? So there are approximately 150 we have identified to date who are caring for these patients and with whom our teams are actively engaged. They're primarily pediatric endocrinologists or endocrinologists, and this suggests that the patients under their care are seeking management for obesity. And as I shared earlier, these patients are looking for a treatment that can help. We also know these patients are clinically and genetically confirmed with BBS. The territory manager team will have these physicians as a primary focus at launch. Next slide. So talking a little bit about the territory manager team. The team is led by 2 strong leaders with deep launch and rare disease experience. Howard leads the West and Ann leads the East. The TM team or territory manager team is a group of entrepreneurial salespeople. They're deeply committed to helping patients and physicians and they understand what it takes to help shorten the diagnostic journey of patients living with rare disease. In fact, the team of 12 had such an impressive early success in identifying patients, within the first few months, we decided to expand the team from 12 to 16 to allow for greater reach throughout the entire road map. In my experience within this space, this activity level was remarkable. And it's the result of hiring an experienced team in rare, the unmet need in BBS as well as an indication that there are a significant number of patients with BBS in the community. Next slide. As is the case in the rare disease, there is tremendous variability among physicians and their level of disease understanding. And these physicians have a spectrum of understanding both on BBS and the associated obesity and hyperphagia. Some physicians understand the problem well like Dr. Haws and Dr. Conroy. Others need to be educated on the impact of hyperphagia on quality of life, the MC4R pathway, and ultimately IMCIVREE, and it's the job of this team to close that gap. We know it's incredibly important to engage with health care providers, and it's equally vital to engage with patients and caregivers. So now I'm going to talk a little bit about our patient engagement. Next slide. As I noted earlier, pre and post-launch, we're focusing on patients with BBS diagnosis and their caregivers. We're ensuring they are engaged with our high-touch patient support service team. We're collaborating with the patient advocacy groups to improve education, and we're providing disease education through various marketing initiatives, including speaker programs delivered by physicians, paired with patients and caregivers who are living with BBS. In fact, as of our fourth program, which just concluded this afternoon, we had 42 patients and caregivers attend these 4 programs in total. We have also, through digital marketing efforts, had 253 patients and caregivers opt in to receive further education from Rhythm. Next slide. In addition to the field-facing teams and marketing programs, there's a suite of initiatives and engagement opportunities that provide sound education and surround sound education of both physicians and patients and caregivers, which is critical as we know, in a rare disease market. Next slide. We know in rare disease, there are many decision points along the journey to treatment. We're educating physicians along the spectrum of disease understanding. We know that many of these physicians understand the problem, and we'll educate the others to understand. I know when they do, they want to prescribe IMCIVREE. They want to prescribe IMCIVREE first-line because of the efficacy and the targeted nature of the drug. As Jennifer noted, the market access and patient services teams are critical along this journey as is the physician commitment to that process. These patients and families frequently have a frustrating path to diagnosis. We have the right launch strategies, organizational structure and focus to support patients at every point along the journey. Once diagnosed, patients have told us they're waiting for a treatment to help them with the hyperphagia and the obesity. And they've also told us they would ask their doctor for IMCIVREE. We are there to provide personalized support to ensure a positive experience with Rhythm and IMCIVREE. And we're excited as an organization to be able to help patients living with BBS and their families to achieve a better outcome. And with that, I will turn it back over to David.

Great. Thank you, Sarah. Next slide. So I hope what you're taking away from today's program is back to the slide you've seen a couple of times, these 3 different buckets, if you will. Bardet-Biedl syndrome, like many rare diseases, it's a devastating disease, as we heard from Mary and amplified by Dr. Haws and Dr. Conroy's description, the hyperphagia and severe obesity, although at first glance, you might think for individuals who are suffering with end-stage renal disease, in some case, blindness in a very high percentage or progressive loss of vision in a very high percentage. But I think Mary's description of that as bad as those manifestations of the disease are. There's -- the health care system has options and things to do to support, but the hyperphagia and severe obesity with existing comorbidities, there's nothing there. And the stigma and the challenge of living with that in a world that's not supportive is devastating. And nothing really works for this. There are no therapies in these patients. Again, as was highlighted, intense efforts can result in weight loss, but as Bob said, does not result in a sustainable weight loss. And so the need for something that can alter the course of this disease, mitigating the hypophagic and then impacting, hopefully, the weight. And even if that's only a stabilization, is really a critical, critical need here. So the solution, again, most of you or many of you know the data from our Phase III, we presented today, the data from our 2-year follow-up. I know there was one question just as to -- we presented data from 19 patients, and Bob had highlighted that 26 patients completed the trial. We actually have 34 patients in total and are currently in our long-term extension study. We reported data on the 19 patients who, as of October, which is when the data cut was done, had reached the 2-year time point. The full data set, the full data cohort completes in March of this year. And so at that point, all those patients will have a full 2-year follow-up, and we'll look forward to updating that. But all of this information, I think, gives us some increasing confidence that setmelanotide IMCIVREE has an opportunity, I think, to make a real difference in the lives of these patients and their families. And so finally, on the -- are we ready? And I know there's been a lot of questions. We started our initial commercial experience, if you will, with the POMC, LEPR receptor and PCSK1 biallelic cohort. We knew from the beginning through fairly extensive genetic testing that those patients, one, they were not preidentified, they needed to be found through genetic testing and the frequency prevalence in the population was low. And so there is a low hit rate. We will find those patients over time, particularly as testing becomes more common. There's a growing awareness already, obviously, in the importance of genetic testing in these patients with early onset obesity and hyperphagia. But that's going to be slow. And so I think that's left some questions as well, you're moving into Bardet-Biedl. Is that going to be the same experience? And I hope what you're taking away from today, it's a completely different experience. And it's a completely different experience for a couple of reasons. One is our confidence that the numbers that we have projected is on the conservative side is growing, and we can walk through the different data points that inform that. You heard some of that today. That's one. Two, the fact that the syndromic nature of this does mean that there's a better opportunity even if it's still painful and often delayed, there's a better opportunity for these patients to get a diagnosis. They may have to see multiple specialists before somebody connects the dots. Ophthalmologists, nephrologists like Bob, when they see these patients, there's characteristic findings and when they get the history of the early onset obesity and the hyperphagia, and if you put together kidney and eye findings, often leads to genetic testing. And again, the diagnosis is made. So we're starting in a world where many, many more patients are diagnosed but it's also clear that there are many -- the vast majority of patients who are undiagnosed. And I hope what you're taking away as you listen to Sarah and Jennifer is an understanding that there's a road map here that unlike a number of the diseases we've worked on a number of years ago, where there weren't the same tools in that sense and the ability to, in a very targeted way, get to physicians who have seen patients, who are actively caring for those patients. And the 350 patients we've identified, there may be some -- for sure, there's some overlap with the 500-plus patients we've talked about that are in the group's registry. But for sure, there's not 100% overlap. And so even just with that small Venn diagram view of the world, that tells you that, that world is significantly larger. So -- and I'll just close, Sarah mentioned this in her experience, my experience as well, having worked on a number of the launches you saw up there on the slide. It's unusual in the world I've lived in a number of diseases to start with this number of patients, 350 patients plus, who are with a reasonably high level of confidence in -- under care of physicians who we were in contact with and have an ability to engage. So we feel really good about the starting point. I hope again, that's a clear message that you're taking away from today and really quite optimistic about the impact that we think we can have and very much looking forward to the PDUFA date on March 16. So with that, we're going to go to a Q&A, and we have a few questions, not quite as many as we had for the first round. I don't know, Dave, are there any other questions that you have there. So we have a couple of questions here.

So Jennifer, first one. So how is reimbursement? And is it different by type of coverage, whether it's Medicaid, Medicare or commercial?

So one piece I did want to outline upfront is that for the initial approval, we did not have a lot of field resources deployed, which includes the fact that we didn't have the corporate accounts team early on ground engaging with payers. However, with that said, through the efforts of our patient support team, we have been successful in terms of being able to gain reimbursement for patients with scripts, both on the commercial as well as Medicaid side. So we're very happy with that. We've had 1 patient who was a Medicare patient that we have yet to get reimbursement for. But I will say that in terms of the patient population that we have diagnosed for the BBS patients, they do skew on the younger side. So we believe that the vast majority of patients will be covered by commercial as well as Medicaid.

Perfect. And Dr. Conroy, thank you for still being with us here. Can I ask you one question, an additional question? So would the undiagnosed population have a similar burden of symptoms as diagnosed patients? Or is it possible that they experience a lesser burden? In other words, are we identifying those most severe who just, of course, come to attention? And from here on, it's only going to get more difficult?

I think there might be other people out there who are undiagnosed, not because the obesity burden isn't as significant or the visual impairment isn't as significant. I just think they might have not gotten to that point of getting the attention of their primary care doctor to follow through with genetic testing. We all know a lot about BBS and it's on our minds. And when I see a patient for obesity, it's something that's in the back of my head, making sure I'm ticking certain boxes when I'm asking about different features and symptoms and things like that. But that's not the case for everybody, especially nowadays, when there's such a high percentage of children who have obesity, it's hard to, like, as a general pediatrician to always think about that smaller 5% bucket that encompasses all organic causes of obesity. And so I feel like it's not that they're undiagnosed because they're not as severe. I just don't think they've hit that point of getting the appropriate testing to have the diagnosis.

And Bob...

Another comment, I think that's really good. I had an interesting experience of diagnosing a child with Bardet-Biedl syndrome. And as I was going through the charts, there is a note from a geneticist from several years before that time. And the geneticist said, I don't see any reason to try to figure out if this is Bardet-Biedl syndrome or McKusick-Kaufman syndrome because it doesn't make a difference. There's no treatment difference between the 2. Why do I need to worry about what -- why should I spend the money on genetics? And that's a sad statement, but it's corrected now because now we have a reason to find out, because we have a therapy that can make a huge difference. And so now that there's a therapy, I think there will be a lot more doctors saying, "I want to know if you've got Bardet-Biedl syndrome. I want to know if this is the right diagnosis because I can offer you something that can treat this problem." And so I think what setmelanotide is bringing to the BBS community is hope and reason for doctors to want to know what this diagnosis is and how they can treat it effectively.

That's great. I'll just add one additional anecdote from my own personal experience, I was still working on Gaucher disease, which many people know, which was one of the early rare diseases that came to attention with a therapy. And 30 years later, we were identifying patients in the United States, in New York City with full-blown Gaucher disease, classic manifestations of the disease and later in life. And they had just been missed. And the point is that in a rare disease, despite doing a lot of education, it's often the case that if you're seen by physicians who don't see these indications frequently -- we just lost our screen here, so I thought we were off the air, but I think we're still good. We just -- you're back, sorry. The patients, in other words, despite doing a lot of work, patients with full-blown disease remain lost in the system. And it's not until they see a physician who connects the dots. And if they're lucky enough to get to Marshfield Clinic, that happens, but many don't right away. So our job, as a company, is to improve the ability of this patient -- of the physician community to connect those dots. One other question here for Jennifer. Do we expect payers to gain reauthorization on measures of obesity or hyperphagia? Do you see them differentiating between those 2 presentations?

So in terms of what we have experienced in the initial indication in terms of PAs, it has been very much according to label. And regarding the prior authorization, it was also according to the label of what we had for the [ PPL ] patient population, which was a weight loss measure at a certain time point. The clinical trial design for the BBS patients was very different. So what great would look like for us just in terms of PA would be similar in terms of really matching what we got in our label, but also the evaluation of clinical efficacy being shown really through the impact on hunger and/or obesity. So I think in many different diseases, you need to show that you're having some type of clinical impact. And for us, that would be what we would really look for just in terms of requirements for BBS patients.

Great. And Bob, another question for you. We -- people, of course, the GLP-1 class has become available now and is a treatment for patients with general obesity. How do you -- what role do you see for a GLP-1 in the treatment of patients with Bardet-Biedl syndrome?

So in my conversations with people, I have not heard of anyone who's had success with GLP-1 with BBS. Now that might be because it's just not being used enough. But I'm unaware of it's being used. I do wonder about combination drugs with setmelanotide and GLP-1 together. But I don't know of any one in our registry who has been on a GLP-1 had a favorable response yet.

Okay. Thank you. So I think that is the last question that I have. I don't know, Dave, are there any other questions on the chat room?

There are not.

Okay. So we'll wrap it up there. So again, in closing, thanks to all of you for tuning in. Thanks to Mary and Bob, and Rushika, for helping us better understand this disease. Thanks to Sarah and Jennifer for updating people on what I think is a tremendous progress that we've made, and we very much look forward to updating all of you as we progress forward here and hopefully, back with good news on March 16. So with that, we'll sign off. Thank you.