Thank you for standing by. Welcome to Rhythm Pharmaceuticals results from phase II Prader-Willi Syndrome Trial. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question, you will need to press star one one on your telephone. You will then hear a message advising your hand is raised. To withdraw the question, please press star one one again. Please be advised that today's conference is being recorded. Now it's my pleasure to hand the conference to David Connolly with Investor Relations at Rhythm Pharmaceuticals. Please proceed. Thank you, Carmen. I'm Dave Connolly here at Rhythm Pharmaceuticals. This morning, we issued a press release announcing positive interim data from our phase II trial of setmelanotide in patients with Prader-Willi syndrome. That press release is available on our website. Our slides for this call can be accessed and controlled by going to the investors section of our website at ir.rhythmtx.com. On the call today are David Meeker, our Chairman, Chief Executive Officer, and President of Rhythm Pharmaceuticals, and Dr. Jennifer Miller, pediatric endocrinologist at the University of Florida. On slide three, I'll remind you that this call contains remarks concerning future expectations, plans, and prospects, which constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed on our most recent annual or quarterly reports on file with the SEC. Any forward-looking statements represent our views as of today and should not be relied upon as representing our views as of any subsequent dates. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to David Meeker, who will begin on slide five. Thank you, Dave. Good morning, everybody. Thank you for joining on a Saturday. We're thrilled to have Dr. Miller joining us this morning, despite a 1:00 A.M. arrival last night. Dr. Miller will present the six-month data results from our open label study of setmelanotide in patients with PWS at an American College of Endocrinology poster session at 12:45 P.M. Chicago time today. The headline is that we saw a consistent response to setmelanotide across four key measures. BMI and BMI z-scores decreased with a corresponding decrease in fat mass while preserving lean mass, and we saw a consistent decrease in both their hyperphagia scores and their anxiety. These results reinforce the rationale and our conviction to advance MC4R agonism to phase III in PWS. This morning, we will present the data that will be in the poster, along with some additional color. Before we do that, I want to remind you of Rhythm's three key pillars on slide six, underlying our strategy of fully developing therapies for diseases defined by impaired signaling through the MC4R pathway. We will continue to work on genetic causes. We are pleased with the start of our launch into acquired HO, and as you will hear today, we believe we can make a significant difference in the lives of patients living with PWS. The epidemiology of PWS is reasonably well understood, and we did our own analysis following the methodology outlined on slide seven. We estimate a prevalent population of 12,500 to 16,000 in each of the U.S. and Europe, with 80%-90% of patients having MC4R pathway impairment for a target population range of 8,500-12,750. In the appendix, there are two slides that walk you through our bottoms-up methodology with citations. Now let's move to the data highlights on slide eight. We are, as promised, showing you four metrics which in their totality, we believe capture the full picture of the benefit of treatment with setmelanotide. This is a complex disease characterized not only by the hyperphagia and associated obesity in patients who are not severely calorie restricted, but also challenging behaviors including rigidity, obsessive compulsive disorder, a tendency to emotional breakdowns, and in some patients, more violent behaviors. In addition to BMI in adults and BMI-Z in children, we record changes in their hyperphagia questionnaire for clinical trials, the HQCT score, the currently accepted hyperphagia score. The HQCT is a nine-item caregiver assessment, with each item being scored on a zero to four-point scale with a possible maximal score of 36. The higher the score, the more severe the hyperphagia. In the FDA review of VYKAT, the agency's anchor-based evaluation of the study data found that a plausible range of clinically meaningful change thresholds in HQCT total score is between four and 7.5 points. The Prader-Willi Syndrome Anxiousness and Distress Behaviors Questionnaire, or PADQ, is also a caregiver-reported assessment, with 14 items scored on a scale of zero to four and a maximal potential score of 56. The higher the score, the more severe the patient's anxiety and level of distress. An 11-point or more reduction in score is considered clinically meaningful. As shown on slide eight, the mean BMI decrease at six months across all 17 patients was 3.06%. Adult patients had a mean BMI decrease of 3.11%, and the seven pediatric patients, some of whom experienced significant growth during the six-month period, had a BMI-Z score decrease of -0.35. The mean decrease in fat mass was 4.19% for the 16 patients with scans while preserving lean mass. Notably, eight of 10 patients with moderate to severe hyperphagia, defined as a HQCT score of greater than or equal to 13, had a seven-point or greater decrease in score. As a reminder, as shown on slide nine, this is an open label study of setmelanotide dosed up to a maximum of five milligrams as tolerated for a period of six months in patients age greater than or equal to six with PWS. Originally, this was a six-month study, but we had amended the duration to be one year plus an open label extension. This six-month interim look at the data was pre-specified. Slide 10 shows the patient demographics in this position. A total of 18 patients were enrolled. Patient number four, as we indicated on our December call, discontinued the trial early for personal family reasons. All remaining 17 patients have stayed in the study, and that is the data we are presenting today. There were 11 adult patients and seven patients less than 18. Seven patients had diabetes. Two patients had extremely poorly controlled diabetes, and three patients were treated with insulin, which can contribute to weight gain. 14 of 17 patients were treated with growth hormone, which has positive effects on body composition. The patients were living with severe obesity, with a mean BMI of 39 overall and 41.1 in the adult patients. The mean BMI z-score in patients less than 18 was 4.15. The average HQCT score was 12.83. As noted, a total of 10 patients had a baseline score greater than 13, a level that correlates with moderate to severe hyperphagia and that has been used in prior hyperphagia trials to define patient eligibility. The mean PADQ score was 29.9. A total of nine patients were on BiPAP. Slide 11 shows the BMI plot for all 17 patients. 14 of 17 patients showed a decrease in their BMI over the course of the six months. The next two slides look at the BMI and BMI z-score changes in adult and pediatric patients respectively, with their corresponding DEXA scan results at six months below each patient. The dark blue bars represent the% change in fat mass, and the light purple bars show the% change in lean mass. Beginning with the adults on slide 12, you can see that 10 adult patients had a mean BMI% decrease of 3.11%. Of note, all patients had a decrease in BMI over the six months, with the exception of patient one, who, as you remember from the December presentation, had severe uncontrolled diabetes, among other medical problems. Her weight has remained stable to down after her initial increase. If you look at the DEXA scan results shown below each patient, the nine adult patients with an available DEXA scan had an approximate mean change in% fat mass of -7.4%, with relative preservation of lean mass, and in the majority of cases, the decrease in fat mass% exceeded the% decrease in BMI. The next slide shows the change in BMI z-scores for pediatric patients. Importantly, most of these patients were on growth hormone. Mean BMI z-score change was a -0.35, with a reduction of greater than 0.2 being viewed as clinically meaningful. Six of seven patients had a BMI z-score decrease of approximately 0.2 or greater. DEXA scan results must be interpreted differently in pediatric patients, as they would be expected to add both fat and lean mass as they grow. Girls will add more fat mass than boys. Patient five did not have a measurable response to treatment, although his BMI has fluctuated significantly during the trial. The other patients showed a variable response on DEXA, with both fat and lean mass decreasing in some and increasing in others consistent with their growth. Moving to the next two slides, we see the same BMI and BMI z bars at the top for each patient, with the corresponding HQCT and PADQ scores for each patient on the two panels below. On slide 14, we see the adult patients. HQCT scores decreased meaningfully in all eight patients with elevated baseline values. Two patients had baseline scores of zero, with no opportunity to improve. Six out of six patients with scores greater than seven, and therefore an opportunity to show a seven-point or more change, all had a change of seven or greater. The PADQ score results showed a similar pattern, with all but two patients who had low baseline scores showing a decrease in their score, and of the eight patients with a baseline score of 11 or greater, and therefore the potential to show an 11-point or greater change, six out of eight patients did show that change. Moving to slide 15, we show the results for the pediatric patients. HQCT scores decreased in five out of six patients with baseline elevated scores, and they decreased by more than seven points in three of five patients with baseline values greater than seven. Patient five did not show, as noted, a clear clinical response on any of the four clinical assessments. Again, the PADQ results show a similar pattern, with six of seven patients showing a decrease in their scores from baseline and four of seven patients a greater than 11-point decrease. Patient number eight missed by one point on both the HQCT and PADQ measures from reaching the seven and 11-point thresholds, respectively. On slide 16, we show the safety results. The drug was well-tolerated, with most patients being on four or 4.5 milligrams. Injection site reactions and hyperpigmentation were most commonly seen. I would now like to move to Dr. Miller and ask her a few questions before we go to more general Q&A. Dr. Miller, thank you for joining us today. Thank you for inviting me. I want to acknowledge all the work you do for the Prader-Willi community. You have participated in most of the clinical trials which have been run in this population, and as we at Rhythm have come to appreciate, these are very challenging trials to conduct. Indeed, they are. My first question is just in general, what do you see as the most meaningful results to date in this study? I think the most meaningful results to date are the fact that everything is moving in the same direction. There is consistency across all of these measures between weight, BMI, DEXA results, as well as HQCT scores and PADQ scores. That's very positive to me. Most patients seem to have a relatively consistent response to treatment across the different outcome measures, with the exception of patients one and five. I know we discussed these patients on the December call, but can you remind us a little bit of sort of who they are and what was challenging about these patients? Yeah. Patient 1 has uncontrolled diabetes, very poorly controlled diabetes with an A1C that's ranged between 14%-15% during the course of this time. She's non-compliant with diabetes medications. I insisted that mom be the one to give her the setmelanotide for the trial. I'm not sure of the consistency there either. She and her mom both report that even though her weight has not decreased as they hoped, that she seems happier. She's moving more. She's actually going out of the house and has a job now, which she wasn't doing prior to the trial. They're actually quite thrilled with the results, even though she has not had an improvement in weight or BMI or DEXA scan. Again, I don't know if that's compliance or something else. Then patient 5 had a very difficult social situation. A lot of traveling, moving. He was in high school where people were giving him food. No one was supervising. It was just a tough time during the course of this time because there was so much social upheaval within his life. Again, parents are very pleased. Both of these patients remain on drug and remain on the trial because both parents perceive a benefit. It may not be the benefit that you and I wanted to see, and the benefit in terms of BMI and weight and HQCT score, but it is a benefit. Both patients are consistently seeming happier, having less meltdowns, easier to deal with. When they do have meltdowns, they are certainly shorter-lived. I remember the patient number 1 gained their weight immediately, pretty quickly coming into the trial. Right by month three. She's been stable. Since then she's been stable. Yeah. She's gone down just a smidgen, for the most part, she's been stable. She was never stable before. I've known her her whole life, this is the first time we've seen stability in weight gain, I do actually think that's a win. Right. It looks like she did have a decrease in her HQCT. She did. from 20 baseline to eight. Then, as you said, patient five, perhaps representative of just some of the challenges and. Yes, absolutely. other situations. Can you talk a little bit about factors which may cause visit-to-visit fluctuations despite a general trend towards improvement? I think there's a lot of factors that can cause visit-to-visit fluctuations. Travel, of course, being a big one. We were having these people come every month. They're coming from all over the country for this trial. Travel is stressful and people tend to eat not normally when they're traveling. There's a lot of constipation within this population that worsens with travel. A lot of edema, particularly peripheral edema or lymphedema, which worsens with prolonged travel. I think all of those factors contributed to weight fluctuations, how bad their edema was, whether they had to use the bathroom regularly, that kind of stuff. I also think that things like school situations, school holidays, and new teachers, and things like that, of course, play a big role in variations from visit to visit. Unfortunately, we've had several families during the course of this trial that the parents have gotten profoundly ill, and that also has affected this because, if the primary caregiver is not available to really be the one making sure that everything is happening the way that it should, you can get some variability in results. Okay. How would you characterize the patient population as compared to the broader Prader-Willi population, knowing that some of the more challenging patients are referred to you? I know we've gotten this from a number of people who follow Rhythm. Yeah. These were the worst of the worst patients for me. They were patients, as I said in December, that did not qualify for any other treatment, that we had tried everything else on, and I felt like I was at the end of what I could do. That made this a particularly challenging population to deal with, being that they were so severe, their BMIs were so severe, their behaviors were so severe. I do think they are representative of a subset of some people with Prader-Willi syndrome. I don't think they're entirely representative of my whole patient population, by far, but they definitely are representative of a big subset of people with Prader-Willi dealing with obesity, uncontrolled diabetes, hyperphagia, that kind of stuff. They speak to the huge unmet need here. They do speak to the huge unmet need. Can you talk a little bit about what you would expect to see in a placebo group with regard to changes in any of these scores? I mean, the fact that they've been in a trial, what impact do you think that has? I honestly don't think it has any. At the beginning for sure, I know that there is a very strong placebo effect in Prader-Willi. We've documented that in multiple trials. However, this far out, that placebo effect is gone. The fact that these results have remained consistent over at least six months, and for some of these patients now 12 months, is really encouraging to me. I think placebo's going to show nothing. I think by six months in, you should see no changes if not increasing. Well, you should see increasing in weight and BMI, increasing in body fat as is typical for the natural history of the syndrome, and behaviors in hyperphagia should not change. Great. Last question. Now that we are six or more months into the trial, what is the general impression of the patient and their family with regard to the changes they've seen on treatment? Everyone's really thrilled. Very thrilled. As I said, all 17 patients have remained in the trial, which is remarkable considering how much we were asking of them during the trial. They are happier in terms of, most of them, especially about the weight control and hyperphagia changes that they're seeing. The other big piece of this is that the kids and adults are actually becoming more physically active. They're choosing to become more physically active, and that's huge. They're purposely going out and doing stuff. Some of the adults have gotten jobs, which they weren't doing before. Parents report that in situations where their kid would normally have a meltdown because things didn't go their way, they're able to sort of reason their way through it and not have a meltdown. It's been quite remarkable. The behavior changes and the positive mental health changes that we've seen have been consistent across everybody. Some of these individuals have even been able to come off of their, not all of them, but some of their atypical antipsychotic meds or come down on those medications, which is huge as well. People with Prader-Willi, as many people know, are just polypharmacy at the extreme. It's nice to see that we have some mechanism to improve quality of life in this population. Great. Thank you. I mean, it highlights again that no one measure captures the benefit. No. Okay, just to wrap up. Thank you, Dr. Miller, for that. In summary, I'll start by acknowledging this trial has limitations. It's a small open label data set. However, I think as you've heard, we're pretty excited about the results to date. All four measures in the majority of patients improved, which is strongly validating in terms of overall clinical benefit. The magnitude of the mean BMI change in adults was modest, but let's put that in some context. The best data to date historically in Prader-Willi, as we discussed on the December call, has been the beloranib data. As shown on slide 18, you can see the weight decrease at six months of 4%-5% in the low and high dose groups respectively. The HQCT results showed a six to seven-point decrease on average. Importantly, the placebo patients gained, as Dr. Miller highlighted, would be expected given the natural history, gained 4% in weight. The HQCT results in the placebo patients showed an initial change consistent with the placebo effect, which had returned to baseline at six months, suggesting that any placebo effect was gone by that time point. Despite the absence of a control group, our results compare favorably with the results shown in that trial. When you factor in that the beloranib study was only in patients greater than equal to 12, with a minimal HQCT score of 13 or greater, and excluded patients with uncontrolled diabetes, for example, including those requiring insulin, and that only 40%-45% of the patients were on growth hormone, that trial may have selected for a population more likely to see weight change and improvement in HQCT. In summary, what do we know? We know that the MC4R biology is part of the disease. The improvements in BMI and BMI-Z, the consistent or even more pronounced decrease in fat mass, the consistent clinically meaningful improvement in HQCT, particularly in patients who had baseline scores greater than 13, accompanied by corresponding improvements in the anxiety distress scores, are highly validating for a meaningful improvement in the disease. There's a reason these patients want to stay on treatment. These results, number three, were observed in a potentially more challenging Prader-Willi population than may have participated in some of the earlier trials. Four, finally, the data strongly support moving to a phase III program with confidence that we can achieve statistically significant and clinically meaningful results on both hyperphagia scores and weight-related measures. With regard to next steps, as previously discussed, we will proceed to phase III clinical trial with a final decision as to which therapeutic agent to be made later this year. We have received many appropriate questions on our development strategy. We started the Prader-Willi program believing the MC4R pathway was central to the hyperphagia and weight gain seen in Prader-Willi. That has been confirmed. The recent VYKAT approval for hyperphagia establishes a pathway for approval, which is more efficient, four to six months in duration than a weight loss trial of 52 weeks. We can imagine running two trials, one focused on hyperphagia with weight and DEXA results as key secondaries, and a second focused on BMI and BMI-Z endpoints with DEXA and HQCT scores as key secondaries. These plans will all be finalized, further finalized after discussion with the FDA. On that, we will now open the call up for general Q&A. Thank you so much. As a reminder, to ask a question, press star one one on your telephone and wait for your name to be announced. To remove yourself, press star one one again. We ask that you please limit yourself to one question. One moment for our first question, please. Comes from Tazeen Ahmad with Bank of America. Please go ahead, Tazeen. Okay, great. Good morning. Thanks for taking my question. I wanted to ask about the evidence that you're seeing of continued improvement over time. Can you help us get a sense about what the trajectory of weight loss has been, let's say from month 3 to month 6? I'm asking mostly because it seems like physicians want to see something around 5% or more in the range of weight loss, sorry, or BMI reduction for these patients. That's a question for both David and Dr. Miller as well. Thank you. Yeah, thanks, Tazeen. Yeah. This is not HO, and I think we all got a little bit swelled there with HO, given the dramatic and profound ongoing response in that setting. Your first part of the question was, what's the general pattern? The pattern is down. The mean at 3 months was about 1.5% decrease, and the mean at 6 months was 3%. As I think most of you know on the call, I'm not a big fan of mean values in very small data sets because, small number of outliers can skew all that, but the general pattern is very clearly down, albeit at a much more gradual overall pace. Then, I'm sorry, what was the other part of that? The 5%. The approval hearing, this is very clear, and I think, given that Prader-Willi is not general obesity, it's not HO. The regs as we have highlighted on previous calls in answering this question is a 5% placebo-adjusted. At 3% at six months and if you use a 2%-4% increase in a placebo group, which would seem to be very reasonable, and I'll ask Dr. Miller to comment on that, I think the possibility that 52 weeks we could clear a 5% placebo-adjusted change in weight is extremely high. One last thing before I turn it over to Dr. Miller. Rare diseases, approvals, regulatory reviews are about the totality of the evidence. You don't rise and fall on one single measure. Given the unmet medical need here and the consistency across results, again, I think we'd be very well-positioned to make a strong case for the clinical benefit here. Maybe, Dr. Miller. I 100% agree, and I was going to say something very similar because right now we don't have anything that can get BMI down at all. Other than severe food restriction, locking people up, locking their kitchens and refrigerators, putting them in special institutions where they're on a 600-calorie diet. Those are not sustainable nor feasible solutions. This offers a sustainable solution with a continuing decline in BMI and BMI-Z. I actually view this data as really positive. I also got spoiled by HO and wanted to see more than a 5% loss, but it was slower and steadier in Prader-Willi syndrome, and people are happy with that. The parents and the individuals themselves are pleased with the results. Thank you. Next question. One moment, please, for our next question. It comes from the line of Phil Nadeau with TD Cowen. Please proceed, Phil. Good morning, Liz and Ara. Congratulations. The consistency in particular is really impressive. Dr. Miller, you made the comment that this isn't a typical Prader-Willi population. It's maybe somewhat more severe than normal. We're curious how you think the results would therefore trend in a more normal population. I guess we could see it going either way in that maybe they're easier to treat, so you see bigger BMI and hyperphagia reductions. The opposite, if there's less room for improvement, maybe there's a ceiling effect. Curious to get your thoughts on that. Thanks. Yeah, I think you're right the first time. I think actually they'll probably be a little bit easier to treat, you'll likely see more profound effects of the drug than you are seeing in this population. Again, these are sort of my worst of my worst. I do think these represent a very significant subset of individuals with Prader-Willi from across the country and across the world. These individuals are not unique in any way. They're fairly unique to my patient population in that they are the worst of the worst for my patient population. Overall, these are fairly common problems that we see with Prader-Willi syndrome around the world. I do think if we include people that are a little bit more mild, the effects will be even more dramatic. That's really helpful. Thank you. Thank you. Next question. Our next question is from Derek Archila with Wells Fargo. Please go ahead, Derek. Hey, good morning, and congrats on the data. Yeah, just to your comments, David, as you think about the development plan for potentially maybe two trials or two different types of trials, I guess, how do you anticipate maybe different enrollment criteria? It seems like, HQCT of greater than 13 for a six-month trial seems very reasonable. But for a 12-month trial, maybe focused on BMI, would you expand criteria beyond greater than 13 HQCT, or would you have some sort of BMI baseline criteria? That would be helpful to know. Thanks. Yes. I'll let Dr. Miller chime in here. Initially, yes. To run the HQCT with that as a primary endpoint, by definition, we'd do what everybody else has done, which is restrict it to patients who have a certain level of baseline severity. I think if you remember from the VYKAT, they even stratified for level of severity above the 13. The higher you are, the worse you are, the greater the opportunity to improve if you have a drug that's actually working there. I think it's an interesting question on the weight trial. To be honest, we haven't gotten any feedback from the FDA and in these kind of diseases, I'm quoting you what's sort of generally required for weight loss trials and what we've been asked for some of our other indications. We'll see if we need to do a full 52-week trial. I would go in again and just make the case that may or may not be what is in the best interest of patient population. If we do, and that's the primary, then yeah, you might want to open it up and not restrict it only to patients with an HQCT greater than 13 because there's clearly patients who have an unmet need will have lower scores than that. Jennifer. I agree. I agree. Patients that are on BiCAT are going to obviously have lower HQCT scores coming in, but many of them still are suffering from obesity and metabolic consequences of obesity and behavior stuff. I think this drug represents a really nice adjunct therapy to that, and so David and I have had some discussions at length about whether or not HQCT should be a primary endpoint or weight BMI DEXA scan. Hence the discussion of possibly doing two different trials to sort of cull out all that information from this population. Excellent. Thank you. Thank you. Our next question comes from Seamus Fernandez with Guggenheim Securities. Please proceed. Great. Thanks for the question. Just wanted to get a sense of if you have a robust sense of the compliance in this trial. It seems like if there were compliance challenges, a once weekly could have a meaningful incremental benefit and probably be quite a bit easier to track from a compliance perspective in the actual clinical study. Just hoping to get a better sense of your tracking of the compliance in this patient population given some of the variability. Thanks. Overall compliance was excellent. People with Prader-Willi have a lot of compulsive tendencies, and they like to take medicines. Having a daily injection was not a big deal for most of them. Many of them, as David mentioned, are on growth hormones, so they were used to already having a daily injection. It didn't bother them. The two that we suspected more non-compliance in, number one and number five, again, both were in difficult family situations. Patient number one was on a once weekly GLP-1 at one point in time. It didn't do much of anything for her, mostly because she didn't take it because she didn't remember once a week to take it. Once a week tends to be challenging for this population, more than you would think, especially more than the general population, because they like to do things routinely. having the routine of doing something daily actually works for most of them. Okay. Thanks, Seamus. Thank you. One moment for our next question, please. It's from Corinne Johnson with Goldman Sachs. Please proceed. Yes. Good morning. Congrats on the data. I guess one question from me, Dr. Miller, you mentioned that these patients are seeing improvements in behavior. I guess, what do you attribute those behavior changes to? Do you think it's a direct mechanism of the MC4R agonism, or is it a result of the broader reduction in food noise? It's a very good question, and I don't know the answer. We did also see it in the HO population as well, and the genetic obesity population. People reported similar things. It wasn't really surprising other than it was surprising to watch it happen. Again, the people that were in this trial were very, very severe. First few months of the trial, throwing things, screaming, yelling. Watching that improve was stunning. Some of the parents really are just beyond thrilled with the changes in this. They said, "I didn't like my child for a while, and now I like them again. They're easier to deal with." I don't know the answer is the long and the short of it, but it was kind of consistent across all the setmelanotide trials we've done. It leads me to believe it's something about the drug itself or the agonism of the melanocortin-4 receptor that does this. I did find it really exciting and nice to see happen. Yeah, maybe to that point, just spinning up. You said you and I have talked about this. I mean, the HO population, this increased desire to do things- Yeah be active, call it energy, whatever, didn't seem to tightly correlate with weight. No. It wasn't just that they've lost- Not at all some pounds- Right are feeling better, so. Right. Exactly. We saw behavior changes there too in a very positive manner as well. yeah. Okay. Next question? Thank you. It comes from Mike Holtz with Morgan Stanley. Please proceed, Mike. Hi, good morning. This is Mike. Thanks for taking our questions. Just based on these results, can you talk about the bar for results at one year? Is it still greater than 5% reduction? Have you had any additional discussions with the regulators? Thanks. Yeah. Thanks, Mike. Just to be clear, we haven't had any discussions with the regulators. What I've repeated, and I feel pretty confident because, again, those are the regs, that a 5% placebo adjusted is the bar in terms of decreasing BMI or decreasing weight. I do, and I'll say it again, this is the kind of setting where it's a totality of the evidence that regulators will look at. It's very important, and that's why we've highlighted on today's results what makes us very excited about this setting is how consistent the results were. It wasn't that we got a little bit of movement on BMI and not much else happened. No, we had directional improvement across all four measures. I think as Dr. Miller highlighted, that's pretty meaningful, and the behavior assessments are a big part of that. Yeah, I think that's the bar from 52 weeks. Thank you. Next question. Thank you. The next question is from Samantha Semenkow with Citi. Please proceed. Hi, this is Ben on for Sam. Thanks so much for taking the question. Just curious, are you seeing any early patterns in age or HQCT or PADQ that might differentiate the patients that responded stronger in the study? Yeah. I mean, I'll go first, and Dr. Miller can tell me if this sounds right. I think for both of those, they tended to move relatively quickly, the HQCT score and the PADQ. Now, to the point that you see placebo effects early on in Prader-Willi. That initial movement, you wouldn't know, was that a placebo effect or not? What gives us confidence is that that initial move has really persisted. I mean, it hasn't even drifted back. Essentially in all the patients. It's held at that initial drop. That, again, is very consistent with what we've seen in the other populations we've treated. Bardet-Biedl syndrome, for 16 weeks, we saw the drop in the hunger scores, and then it just maintained. HO similarly. It wasn't that these scores don't tend to go down over the course of a year. They tend to get the effect, and then that effect persists. I think that's correct. That sounds correct. I would say, I do think the effects on increasing movement and physical activity on purpose, that they're choosing to do more physical activity, happens at about three to six months. We start to see more of that. I'm very curious to follow these results out to a year because that should result in more meaningful changes in BMI as well. Next question. Thank you. Our next question is from Jon Wolleben with Citizens. Please proceed, Jon. Hey, thanks for taking the question. Just one for Dr. Miller. I'm wondering which one of these measures do patients or parents care most about? Honestly, behavior. I think that's a big one. Of course, weight and BMI are very important to them as well. They love seeing the results of the DEXA. When we get DEXAs, they're very excited to go and see those. So, there's a lot of things. I think these families, all of them, have been through a lot with hyperphagia and various hyperphagia-related analysis measures. And so I think that one is not quite as important to them as the changes in anxiety, behaviors, temper tantrums, and body composition. But again, I think the biggest thing for everybody is quality of life. I think quality of life dramatically improves, and that's remarkable. Jon, I just want to highlight again, I think as Dr. Miller said, that's clearly what patients may value. We haven't had questions yet to date or so far on the call about the DEXA scans, but that's the other piece of this which I think I found really compelling here, is that body composition is improving and the percent decrease in the fat mass, which was really consistent. Some of the variables Dr. Miller highlighted that may impact the measurement of a weight and BMI, like edema and water shifts and the like, constipation. Those are transient measures, but they impact how you measure those. The DEXA scan is a more reliable assessment of what's changing. Again, directionally and meaningfully, that fat mass was going down with, which is what we've seen in our other trials with setmelanotide, relative preservation of the lean mass. Next question. Thank you so much. Our next question comes from the line of Paul Matteis with Stifel. Please proceed. Hey, great. Thanks so much, and congrats on the data update. One question on the next steps on the trial side. David, are you thinking that you might try to pursue a randomized withdrawal study, given that that was a path for Soleno and just given the history of those studies having a higher POS? then one quick question for Dr. Miller. When you think about this mechanism, does it make sense that weight loss would continue to build and be linear from month six to 12? Or would you think that most of the benefits would have already accrued on BMI by month six? Thank you. would we do a randomized withdrawal? Dr. Miller's shaking her head. Vehemently. Vehemently. I think if you remember, as I understand it, again, just reading what's public, in terms of the VYKAT trial, that ran into the COVID situation. there's some unique aspects of that whole setting, and they ended up negotiating a randomized withdrawal with the FDA. no, I think we just run a straight-up trial, and I think this data would support the fact that we'd be able to see a meaningful difference there. maybe Dr. Miller, just on from month six to 12. Yeah. I think we've had five patients complete 12 months now, and the trend has continued in terms of weight loss over that time. I expect it to continue to build and to continue to improve. Yeah. To just be clear on that, we haven't released the five patients. Sorry. No. In that five are the patients number one and five. Right. Of course. the other three, to your point, now have continued to trend down, and patients one and five- Stable their situations are stable. That's it, yeah. Next question. Thank you. The next question comes from Joseph Stringer with Needham & Company. Please proceed. Hi, good morning. Thanks for taking our questions. Apologies if I missed this, but how many of the 17 patients at six months titrated up to the 5 mg level? on average, how long was that titration period? then for Dr. Miller, assuming for now that the go-forward option in phase III is the setmelanotide once daily injection, can you compare and contrast this with oral VYKAT in terms of balancing benefit and convenience in a real-world setting? Okay. Maybe just on the dosing here, and Dr. Miller can chime in. I think a significant% of the patients did get up to five. I think where, as I understand it, Dr. Miller, talking to the families, they've sort of settled out in the 4 to 4.5 milligram range- Correct as the point where they feel better. I don't know the- That's correct. I'd say the great majority on 4 to 4.5. Five didn't seem to do much above four or 4.5. in the spirit of less is better, we went down on the dosing because if all things being equal, I'd prefer to give a lower dose to have less risk for side effects. The question about the once a week setmelanotide versus VYKAT is very difficult for me to answer because I don't know the answer. Again, I know that people with Prader-Willi do well with routine, so compliance with VYKAT tends to be excellent in the clinical population, with a real world situation because it's a once a day pills that they take, and they like to put things in their mouth, so that works. I haven't really had a lot of experience with once weekly, either growth hormone, or even the GLP-1s, which we do not use very commonly in Prader-Willi. Simply because the once a week growth hormone is not FDA approved for Prader-Willi syndrome, and so we don't very often get insurance approval, so we use daily still. I just don't have a lot of experience with once weekly injections to know the level of compliance at this point in time. Perfect. Great. Next question? Yep. It comes from the line of Lisa Walter with RBC. Please proceed. Oh, good morning and congrats on the data, and thanks for taking our questions. Maybe one for Dr. Miller. In your experience, for a patient not on treatment, what is the average BMI gain likely to be in adults over 52 weeks? Do HQCT scores also change over time as well? Maybe just one for David. On your phase III plans for Prader-Willi, are you going to move forward with setmelanotide or RM 718? Any color here would be helpful. Thanks so much. You want me to take the first one? I'll take first. Yeah. In general, adults with Prader-Willi tend to gain around 3% BMI per year. That's pretty average. There's some variability there. It can be more, it can be less, depending on environment, of course. If they're in a group home where everything's restricted, obviously that's not the situation, but in free living adults with Prader-Willi, there is a consistent gain in BMI through each year. That's what I would expect to see. What was the second part of the question? No, I got that. RM 718. Okay. I'm just curious, actually, you and I haven't talked about this specifically. As the Prader-Willi patients get older and become more challenging just physically to manage- Yes does that in a home setting, does their weight tend to go up more quickly? Of course. Absolutely, it does. Also they become more sedentary. Their parents are getting older. They're tired. The families are tired of doing this. There's not as much pushback about the food and about the exercise and that kind of stuff. Things just tend to spiral in a very negative way in general. To the general. Yeah. Which makes the results you saw in the adults even more impressive. Even more. Yeah, exactly. In terms of that. okay. Lisa, I think your last question was just on which drug are we going to use? I apologize for still kicking this out because we can obviously use setmelanotide, approved drug, and we've got this data now. as I've said many times, all things being equal, we'd love to do it with the next generation. You've heard some thoughts from Dr. Miller on the pros and cons of a weekly versus a daily. The bivamelagon is obviously a daily oral. those are all considerations. we'll make a decision by the end of the year, or later this year. I won't put a date on it, but all three things are still in consideration. Our next question comes from Raghuram Selvaraju with H.C. Wainwright. Please go ahead. Thanks so much for taking my questions. I guess these are both really for Dr. Miller. When you think about the possibility of combining a drug like setmelanotide or like 718 with any existing component of the PWS armamentarium, what kind of factors are likely to most affect your decision-making process there? Is it likely to be primarily the safety and tolerability profile or the additive or possibly synergistic efficacy that you might achieve there? also maybe could you comment on the specific PWS patient subpopulation for whom, for whatever reason, primarily related to safety, perhaps a drug like VYKAT XR might be contraindicated, and how likely those patients might be to be candidates for therapy with a drug like setmelanotide or 718? Thank you. Yes. Those are exactly the patients that I want on setmelanotide, are the ones that have medical contraindications to going on VYKAT, for the reasons of type 2 diabetes, severe obesity with edema already existing, so that the risk profile of VYKAT would be exacerbated. I think the answer to your first question is actually both of those things. I think one of the things that I look at, as me, is the additive effect of multiple drugs. I like that idea. mechanistically, it makes sense with VYKAT and setmelanotide that there would be a synergistic effect of those drugs. I also, of course, look at safety and tolerability. One of the things that I think is the most challenging for most peds endos who take care or even adult endos who take care of people with Prader-Willi, is that the polypharmacy with psych drugs is humongous, and many, many, many, many, many adults are on atypical antipsychotics, which of course worsen the metabolic profile and the weight gain and the risk for type 2 diabetes. Having something like setmelanotide in the armamentarium that you could potentially lessen those risks is huge. Like I said, we saw one person come off of their atypical antipsychotic completely during this trial, during the six months. We've seen several reduce their doses quite significantly. That alone, I think, is huge for me because those medicines are kind of the bane of my existence in terms of being an endocrinologist, but are necessary in terms of controlling symptoms for patients with Prader-Willi. I think that, again, I think that both factors would come into play, both safety and efficacy, but also the potential additive effects of more than one drug. Lastly is the effects of maybe ameliorating the consequences of a drug that's necessary for a different reason. Great. Thank you so much. Thank you. Our last question comes from the line of Leland Gershell with Oppenheimer. Please proceed. Good morning, and great to see these positive data. Thanks for taking our question. Wanted to ask a question on dosing. I think, David, you had mentioned that these patients had gotten up to, I think, four to four and a half, and I think up to the maximum potential was five per day. I wanted to ask, Dr. Miller, do you think that there would be room for greater efficacy benefit with a more selective MC4R? I guess if we look at the table on 16 of the AEs, are we hitting adverse events that are preventing patients from getting dosed further? Do you think there might be room for greater efficacy in PWS with a more ideal melanocortin agent? Thank you. Yeah. Thanks, Leland. Maybe I'll lead off here and then let Dr. Miller comment. setmelanotide is a highly specific MC4R. It hits MC1, but it has very good potency at the MC4R receptor. It's about 10-fold more potent than the endogenous ligand alpha-melanocyte-stimulating hormone. we've been pretty convinced that it's not clear there's a lot of room to do better in terms of pure MC4R agonism. back to why did we go up to five, and we've done most of our work, as you all know, between one and three milligrams as the dosing regimen. That's the approved regimen. We have safety clearance and have tested this dose as high as seven mgs in patients with our normal volunteers with no problem. going to five, the goal there was to eliminate any possibility that we had left some efficacy on the table by not going high enough. I think this trial's gone a long way to giving us some reassurance that we're in the right range. the last thing I'll just say on the safety, what's again, very reassuring is they seem to tolerate it well, so there weren't any unique safety issues at going to the higher dose. But, Dr. Miller. Yeah. like I said, when people went down from the five down to four or four and a half, it was mostly just because they didn't perceive any additional benefit from being on five versus four or four and a half. I've taught all patients that we don't want to put more stuff in your kid's body than you have to do. if they didn't perceive any efficacy over a couple of months on five milligrams, then we would bring their dose back down to four and a half to see how they did. if they still said, "I think we were about the same on four," we would bring it down to four. Perfect. Thank you. Thank you. This concludes our Q&A session, and I will turn the call back to David Meeker for closing comments. Yeah. Thanks again to everybody for tuning in. Hopefully, you're as excited as we are. Again, it's a tough population, but really encouraged by this initial data set and look forward to updating you on future progress on the program. Thanks, all. Thank you, and this concludes our conference. Thank you for participating, and you may now disconnect.