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

Good morning. I'm Hunter Smith, Chief Financial Officer of Rhythm Pharmaceuticals, and I want to thank you for joining us as we discuss our proof-of-concept data from the exploratory Phase II Basket Study and provide an update on our sequencing efforts. Please note the press release issued earlier today and presentation we're using for this conference call are both available online in the Investors and Media section of our website: rhythmtx.com. Before we begin, I'd like to remind everyone that there will be forward-looking statements made on this call. Actual events or results could differ materially from those expressed or implied by any forward-looking statements, such as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our Forms 10-K or 10-Q or any other filings that we make with the SEC in the future. In addition, any forward-looking statements made on this call represent our views only as of today and should not be relied upon as representing our views of any subsequent day. We specifically disclaim any obligation to update or revise any forward-looking statements. Turning to Slide 3. On today's call are Dr. David Meeker, Chair, President and CEO of Rhythm Pharmaceuticals; and Dr. Murray Stewart, our Chief Medical Officer; as well as Dr. Al Garfield, Head of Translational Research and Development. Before beginning, please note that you can submit questions for this group via the online chat function on your screen, and we will answer them following the presentation. Now I'll turn the call over to David. Thank you.

Thank you, Hunter, and welcome, everyone. Thank you for joining us this morning. So I'm very excited to present today's results, as you probably saw from the press release, and we are presenting positive data on 5 different cohorts, 3 in the head category and SRC1, SH2B1 with response rates in the 30% to 50%. And Murray is going to take you through that detail -- on that data in detail. And what I'd like to do just in a few introductory comments is highlight a few things that I'd like you to think about and hopefully, take away from today's call. So one is there's clearly multiple genetic defects in the MC4 pathway that cause you to potentially be responsive to setmelanotide. And in fact, the multiple may be many. I think we're clearly beginning to open up a whole new list of genes, if you will. Second, we know obesity is a complex disease, and not all patients, some with a pathway defect, will respond to setmelanotide. So again, as we look at the response rates and keep in mind, again, the complexity of the disease in which we are working. Three, we have growing confidence in our ability to identify genes that will respond. And as Al is going to take you through in our genetic section, our epidemiology section, experience and expertise is helping us gain greater and greater confidence about the genes we select to study. There is clearly an evolving paradigm about how do we identify potentially setmelanotide-responsive patients. Not all patients respond to setmelanotide despite having the genetics and the simple concept that genetics are necessary but not sufficient is clearly holding true here. I've been asked, and I'm sure I'll be continued to asked, are you still a rare disease company as the number of patients you are seeking to target increases. And the answer is yes. We are still a rare disease company. Individually, each of these genetically defined populations is rare. In the aggregate, of course, not so rare. And I refer you to other companies in the rare disease space who have multiple different diseases that they are pursuing each rare in the aggregate, perhaps not so rare. That would be Rhythm. And finally, how do we get at this opportunity, and one of the things that is attractive, and certainly, the strategy that we are pursuing is that the process of community building and sequencing of patients is an effort which supports all of the different genetic indications we're pursuing. So it's not as though we have 5 different genes and 5 different strategies to attack each 1 of them. In fact, there's one unified effort, which supports all of them. Next slide. I want to start here, just to remind you, again, obesity is not a choice, certainly not in this case. These are individuals who are suffering from genetically driven disease. And the monogenetic component is a heavy driver of their obesity, leading to the hunger and consequent weight gain. And they're suffering. On the left, you have the Adalissa and Solomon, 2 members of a Bardet-Biedl syndrome family, they both suffer. And as you can see in the quotes there, eating, meal planning, what they're going to eat dominates their life. Katy, on the right here, at 23 years old, 450 pounds. She's a POMC heterozygous patient. One of the cohorts we're reporting out today. And as she described it as a child, the fridge and food was controlled massively, but nobody could understand that I was just desperately hungry. And I just wanted to stop that feeling. And so again, critical that we and obviously, the world, the health care system specifically, understand that these patients have a disease and they need specific therapy. Next. So Rhythm's mission, quite simply, is to change the paradigm for the treatment of rare genetic disease of obesity. And I highlight this because this isn't about just getting setmelanotide through a regulatory process and approved and sold, if you will. This is about changing fundamentally how the health care system sees and treats these patients. So when they see an individual with early onset obesity, they're thinking about the fact that, that patient needs to be genetically tested. And once tested, they realize that there are some things that could be done for that patient, both pharmacologically perhaps and then how they might think about other aspects of their care. Next. So back to the question of rare diseases. And it's actually -- it's a classic rare disease. And the same challenges apply here as applied in some of the truly more specific, if you will, rare diseases. These patients, they're lost in the system, there's little knowledge, little awareness prior to Rhythm coming in with its sequencing effort. There were few of any tools outside of academic centers in terms of sequencing. No treatment prior to the advent of setmelanotide. And in worst case -- this is worse than the rare genetic disease where you know nothing. Many -- unfortunately, we as a society and as health care providers, we think we understand obesity. And simply, you've just got to eat less and exercise more. And that's probably even greater disservice than telling you I don't know what to do. Next. So just a small anecdotal analogy here, if that helps think about this. We know in the United States, an orphan disease population is defined as fewer than 200,000 individuals but there's more than 7,000 rare diseases. And in the aggregate, 30 million or so individuals in the U.S. are affected with a rare disease, so a large number. We're at about 5,000 today. The gene study today read out through the Bardet-Biedl data that we released in December. We put our target population maybe in the range of 5,000 for the United States. Remember, all these are U.S. numbers only. And today, we're going to open up a world where we believe the target population for the diseases we're reporting out on is in the order of 100,000 to 200,000 individuals. So quite a significant difference, quite a significant step-up. But again, individually, each one of these genetic defect is rare. Next slide. So I'm very briefly just going to remind you of our developmental pathway and it started with a biology as most programs do. And not all programs, I think, have the luxury of strong biology. And the MC4R pathway, its relationship to hunger and weight gain has been incredibly well studied, well documented biology. It's just strong and clear, great place to start. Next. In the first 2 genes we selected to study, POMC and LEPR, were selected because, again, the data supported their -- they're linked to this pathway. In a sense, the idea was that if it did not work in POMC and LEPR, it probably would not work, and we would have stopped there. And these are the first 2 patients which we reported out, treated on both case reports where you saw profound weight loss both on the POMC and the LEPR individuals, which led us to the Phase III program. Next slide, where, again, small numbers, we treated 10 patients in the POMC, 11 in the LEPR Phase III trials. And again, very profound reductions in weight, more in the POMC than we saw on the LEPR. There was more variability in the LEPR response. But in both cases, very strong responses. And we went on and added an additional 4 patients to each one of these cohorts. And 12 of 15 in the POMC remain in our long-term extension and 12 of 15 in the LEPR remain in our long-term extension and continue to do well. And one of the things we're learning from that long extension, again, is the durability, unlike many weight loss programs where with intense effort and diet restriction, yes, you can lose weight, but can you sustain it? And many things about that process conspire against you. In this case, we're restoring normal physiology by restoring the tone in the pathway. And so again, the durability of the weight loss has been important. Next. In December, we reported out our Bardet-Biedl. And with 34.5% of the Bardet-Biedl and Alström's patients, who we've studied reaching a 10% or greater weight loss at the end of 1 year. But as we dug into the data and both -- that was associated with a significant decrease in hunger scores. But as we dug into the data, we realized that, that was not telling the whole story. Next slide. In the analysis set, those 12 and older, the 3 Alström's patients, we did not have a responder, all the responders were in the Bardet-Biedl group. So if you focused on the Bardet-Biedl instead, well, how well did it work in Bardet-Biedl? The answer is that 11 out of 28 or 38% had a greater than 10% decrease in weight. But there was 1 more level we needed to go to, which was in that 28 patients, about half were under the age of 18, many of them in that 12 to 14-year-old age range in an age where we know growth occurs, and that growth was confounding the readout. So the purest readout, we believe, with the Bardet-Biedl is to focus on what happened in adults without that high-growth effect, and that's that right box, which says that 8 out of 15, 53% of the adult BBS patients achieved greater than 10% weight loss. And recognizing that a weight loss of 5% or greater, so those between 5% and 9%, also were benefiting and had the hunger reduction, that total was 73%. So again, we came away very convinced and reassured by the fact that there is a strong and clear signal here in Bardet-Biedl, which will support filing. The decision around Alström's is pending. We will -- there's clearly individual patients with Alström's syndrome who have responded. And so we will do more work there. Again, to better understand exactly what we have and the decision on filing is still to come. But clearly, with Bardet-Biedl, we will be moving forward. Next. And the other thing about any drug development program, many drugs or most drugs often fail because of safety reasons. And very reassuringly, and Murray will take you through in greater detail today, there's been a highly consistent safety profile across all of these -- all patients treated and now up to 590 patients. And predominantly skin hyperpigmentation and nausea and vomiting are the 2 cornerstone injection site reactions, some of the subcu injections are seen. But those are the 2 major, and he's going to give you some greater insight in how we see that playing forward and how it can be managed. Next. So this is our standard slide that we show to frame Rhythm. Just to remind you, again, the journey we've been on when I first joined back in the summer, we defined these 3 steps. First is approval of IMCIVREE, which happened in November. That was a validating step, small number of patients, but highly validating. We've got an approved drug, not so many companies have an approved drug. December data, Bardet-Biedl and Alström's, Bardet-Biedl, meaningful opportunity, viable, as I just described. And then today, we're going to look at this third bucket, which is the opening up of what is truly, I think, been a bit of an unrecognized part of the Rhythm story, which is how many other genes do touch this pathway? And what is the true potential of setmelanotide over the long-term. And the blue bar on the bottom, highlighting fact that, yes, all of these populations can be pursued with the same basic effort. Next. So what is that growth opportunity? And Al is going to take you through this in much greater detail. But on the order of 5 million individuals in the U.S. have early onset obesity. The number or percentage of patients in that 5 million based on sequencing data for the 5 cohorts that we're reporting out today, we believe, is on the order of 10% to 15%. So 10% to 15% of that 5 million will have a positive genetic test for 1 of these genes. That does not mean that they will, a priority respond to setmelanotide. Obesity is a complex disease. And therefore, we need a third step to identify the true responders. Next slide. So why is it so complex? I mean, again, it's a bit of reiterating the obvious here. But the question is, you have a genetic defect, is it a pure monogenetic disease? Is nothing else going on? Is it a monogenic contributor, meaning you may have other compensatory genetics that are at play there. Just background susceptibility to being obese or not obese. And then, of course, external influences, which, again, if you -- as an example, if you correct the underlying genetic defect, but did not change your caloric intake, you might not see much change in your weight. Next. So the 3 step, and Murray and Al will both speak to this again, is you got to have a problem, early onset obesity, hyperphagia. You need to have a positive test, step 2, for 1 of the genes of interest. And then the idea is that we would give you a short trial on setmelanotide, and the data is highly supportive of this idea that in that short trial period, we will sort those patients who are responding and those who aren't responding. As Al likes to call it, it's our clinical bioassay. Next. So what have you heard in the short intro? One, hopefully, you understand, this is -- there's a huge unmet medical need here. The MC4R pathway biology is extremely strong and the melanotic development program is building confidence in our expanded opportunity. Next slide. So today's focus, we're presenting a proof-of-concept data. It's the Rhythm's largest data readout from these 5 cohorts, totaling 65 patients in the analytical data set. We achieved proof-of-concept in all 5 MC4R pathway genes. That translates to an estimated U.S. target population across these 5 genes of 100,000 to 200,000 individuals. That's supported by the largest known genetic obesity database of approximately 37,500. The data, both the process of selecting the genes and the clinical readouts support our approach for gene selection and variant classification. And we'll provide an update on the 2 trials that we plan to now go forward with on the back of this positive data, which we'll study, in total 36 genes. And with that, I'll turn it over to Murray.

Thanks, David, and good morning, everyone. Next slide, please. So for this section of the presentation, I'm going to touch on Rhythm's precision approach to obesity. Then I'll take you through the actual data from the 5 cohorts. And I will also show you data on the children with Bardet-Biedl syndrome. And finally, I will take you through the outline of our planned clinical trials related to the MC4R pathway. Next slide. So this schematic is just a diagram showing all the potential things in person's weight. As David said, superficially, it seems quite simple, why don't you eat less and exercise more. But obesity really is complicated. Availability of food, other external influences, all drive you to actually gain more weight rather than lose weight. Rhythm is not going to try and tackle all of obesity. Our approach is very much focused on the genetics starting in the MC4 pathway and looking individuals who present with obesity and hyperphagia. Knowing that setmelanotide's effect is to reduce hunger and increase energy expenditure, both of which will contribute to weight loss. Next slide. So this is the 3-step process that David outlined. I want to go into a little bit more detail. So first of all, when we identify patients, we're really looking for people who have obesity starting at the very young age from 2 years and above. And these individuals would normally be putting on a lot of weight, and therefore, the outside the normal growth of BMI cups as children. Really severe obesity in their age. Many of these children are hyperphagic, which means they're hungry all the time. They start showing behaviors where they're eating inappropriately. They're just grabbing food all the time because even though they will eat food, they will still feel hungry. So the population, early onset, hyperphagic sever obese in adults, that translates to individuals with a body mass index above 40. And in children, we're going to be recruiting people who are less than 18 years of age with their weight curve above the 97%, in other words, the extreme obese children. When we come to step 2, the genes we're looking at are genes involved in signaling in the MC4 pathway. And Al in his presentation will highlight why we're choosing those specific genes in the pathway. But once we've identified an individual with a defect met gene, we need to look at the variant because not all variants are the same. And the classification of the variance we look at is based on the American College of Medical Genetics. They have a standard framework of which to look at a variant in the gene and say whether it's relevant or not. So there's 5 different classifications. At one end, you've got pathogenic and likely pathogenic variants. And obviously, by definition, these variants are going to probably be contributing to the underlying disease, in this case obesity. On the other side of the equation, you have benign [indiscernible] variants. And those variants probably are not contributing. And then the variant classification in the middle is called the VUS or the variant uncertainty and by definition that may mean that the classification means it may be contributed. And actually by this third step really important in our focus because we've got people who have got the phenotype, they've got the genotype. And the question is, will they respond to setmelanotide? So the best way to do that is actually give them a trial of setmelanotide and see whether they respond. So what do we mean by response? So we've chosen 5% weight loss within 3 months is evidence of response. So a few things to note there. First of all, when you're looking at our other studies, we'll be looking over a year. And the question is, can we see a response in 3 months rather than wait for a year. So why did we choose 5%? We chose it for 3 reasons. First of all, 5% weight loss really is clinically significant, makes a difference in terms of other metabolic parameters and morbidity and ultimately, mortality. The other reason to reduce 5% weight loss is, from a regulatory point of view, that weight loss has sustained over a year, and it's different compared to placebo, that is actually the regulatory to get approval for obesity. But finally, in Rythm's case, the reason to use 5% weight loss is, when we look back our programs, we find that people who lose 5% weight loss is a very good sign they will continue to lose weight and go on to lose up to 10% weight loss. So they are the reasons we've chosen 5% weight loss as what we call our responders. For children, given they're growing, we'll be looking at BMI-Z scores. Next slide. So here's the signs behind setmelanotide and setmelanotide works in individuals who've got abnormal signaling in the MC4 pathway. Many of these individuals present hyperphagia, increasing weight because they've got something wrong in the signal. You give setmelanotide at the touch site of the receptor, restores the signaling and thereby reduces the hunger and reduces the weight. So the 5 cohorts we're going to tap today are POMC, PCSK and LEPR heterozygous patients. So what do I mean by heterozygous? The 3 indications before were homozygous. In other words, the bidding was present in both alleles. In other words, there was no signaling due to either allele. And the hypothesis was, well, if you have an abnormal [indiscernible] in 1 allele, is that enough to disrupt the signaling and therefore, potential treatment of setmelanotide in patients who are heterozygous rather than homozygous. The other 2 genes were chosen because of the science-based around what we know about SRC1 and SH2B1. So SRC1, the protein produced related to that gene is a transcriptional coactivator that drives POMC expression. And obviously, if you've got reduced POMC expression, reduced signaling and potential treatment with setmelanotide. The SH2B1 gene relates to an adapter protein that regulates lectin receptor activity. And clearly, if you improve lectin receptor activity, you may thereby improve decision. So the idea is that setmelanotide may improve the weight blocks and result in weight loss in individuals who present with those genetic variants. Next slide. So this is -- this study design of our Basket Study, of which the individuals in the 5 cohorts were part of the study. It was a screening period to check their phenotype and their genotype. And then individuals, adults started on 2 milligrams, and after a couple of weeks went up to 3 milligrams and then continued in the open-label extension. The younger children, those less than 16, started on 1 milligram, then went up to 2 milligrams and then onto the 3 milligrams. The primary endpoint, in other words, where we define the responders, is at visit 6 or week 16. For the completer analysis that I'll show related to SRC1 and SH2B1, completers were included if they reached 12 weeks in visit 5. Many of the patients from the HET have rolled on into the extension study. Next slide. Okay. So now I'm going to take you through the details of the heterozygous patients from the POMC, PCSK, LEPR. This cohort was completed. So for this data set, you'll be sealing the full analysis set. It included 35 heterozygous patients. The mean age was at 39. There were 6 children under age of 18 in this cohort. There were 6% to 8% females, so slightly more females than males. But you can see that these individuals are extremely heavy. The mean weight is over 300 pounds or 143 kilograms, giving a mean body mass index of 45. And I'm reminding you the normal body mass index is 25. And these are clearly heavy individuals. Next slide. So we looked at 3 cohorts within the heterozygous, and this relates to the ACMG classification work. What was the variant that we were looking at? So we wanted to look at individuals who had a pathogenic or likely pathogenic theories that may be contributing to the obesity. And we studied 8 individuals who had pathogenic or likely pathogen variants. We also looked at patients who had variant significance, 19 of those subjects. At Rhythm, we're also interested in looking at a specific unique variant called N221D PSK variant. And we looked at 8 subjects with an N221 variant to see whether certain type will be affected in those individuals. This variant is well described in the literature and is associated with increased obesity. Next slide. So this is the data. Firstly, to point out, the data includes all patients and does include data from 6 patients who discontinued early in the program. Their data was last observation carried forward. So what did the data show? It showed that 34.3% of patients, 12 out of 35 patients, got to the primary endpoint of 5% weight loss within the 3-month time period. When you look overall at the top line there, the percentage change from baseline in weight is 3.7%. This includes data from responders and nonresponders. So if you just look at the individuals who were responders, you can see that they started with a mean weight of 144 kilograms. They lost 14 kilograms which equated to losing 10% of their body weight within a 3-month time period. The next slide shows that we've got 2 clear populations. So those individuals who did not respond, minimal change in weight, 0.4% over the 3 months. Whereas those individuals who did respond, clearly showed a benefit with a mean response of 10% and individuals getting up to over 12% in the 3-month time period. When we look at the time course on the next slide, we can see that we start to see separation after a few weeks so the time get to 12 or 16, we've clearly got evidence of a responder population compared to a nonresponder population. Next slide. In conjunction with the weight loss, we wanted to also see what the hunger data was between responders and nonresponders. So what this graph shows is the same 15-week time period and change in hunger in nonresponders in the red gray dots and the responders in the blue triangles. So what's interesting is the responders and nonresponders have the same hunger score at baseline. So all those individuals came in on the hunger score. The mean hunger score was over 7. We're using a Likert scale where they rate the hunger from 0 to 10. So there's no difference between responders and nonresponders on baseline hunger. But what we saw is, although there was a slight reduction in hunger in the nonresponders of 2.3 points, the responders showed a reduction from values of 7 down to 3. So a 4.5% change in point reduction, which are highly significant reduction in hunger scores and those individuals who then went on to lose significant weight. Next slide. So the question is, who are the responders? So let's go back to the genetic groups we studied. And we've looked at the pathogenic and the likely pathogenic variants. And when we look at the 8 individuals, we can see that 4 or 50% of those individuals with a pathogenic or likely pathogen variant had a clear clinical response, which when we look at individuals with a variant of uncertainty, proportionately, there was a lesser response. However, the 4 individuals or the 20% people who did respond in that category had a very clear clinical response. So although the number of people responding was less in those individuals carrying that variant, if they did respond, they did well. And interestingly, when we look at those individuals through the N221D PCSK variant, again, there was a 50% response rate and those people carrying that variant. Next slide. So the conclusion from the heterozygous patients is overall, there's 35% patients respond with 5% weight loss in 12 weeks. There's clearly separation between nonresponders and responders, supporting our 3-step approach to identify the individuals and the phenotype, look at the genotype and their variant and then do the clinical trial. And we saw that this responder rate was slightly greater in those people who carry the pathogenic or likely pathogenic variant. But as I highlighted, we all saw a response on those individuals carrying the N221 variant. Next slide. So let's now look at those individuals who have the gene defects in the SRC1 and SH2B1. Now it's important to note that these cohorts are ongoing, and this is an interim analysis. And to do that, we're just looking at the completers, those individuals who've got to visit 5 or visit 6, which means they've got at least 12 weeks efficacy data. So by definition, we're excluding some individuals. So we're excluding 12 individuals who are actually still ongoing in this study. But they were early on the process and therefore, haven't accumulated enough efficacy data. We're also excluding 15 patients who withdrew early from this study. So the heterozygotes cohort is completed quite early. Last year, as you know, is difficult for clinical trials, and as we're recruiting the SRC1 and SH2B cohort, it was right in the middle of last year when the COVID pandemic was at high. And unfortunately, we did lose some individuals. So we lost some individuals due to AEs early on. They included hyperpigmentation, nausea and vomiting. But when you look at the safety profile related to our other cohorts, there's nothing to suggest that this cohort was behaving any differently and therefore, when I look at my overall discontinuation across the program, which is normally 90% due to AEs, this increase withdrawal probably relates to the challenge around COVID. But when we look at the cohorts here, what you can see is the mean age is about 30. Again, we've a few adolescents here, we've 5 adolescents in SH2B1 cohort and 4 in the SRC1, slight predominance of females to males. And again, these individuals are very heavy. Mean weight, 250 pounds in SRC1, 270 in SH2B, getting a mean weight of 117, 120 kilograms. And again, body mass index is 44. So let's look at the data in these groups. Next slide. So we'll start with the SRC1. Again, this is completed date. And you can see that 30.8% of patients or 4 out of the 13 who have completed, achieved the primary endpoint of 5% weight loss within the 12 to 16 weeks. The mean weight started at 117, going down to 112. So the overall percentage 3.7%. But again, this included nonresponders and responders. And when you look at the responders, you're seeing a 10-kilogram reduction in weight, equating to 8.4% of the individual's body weight. So on the next slide, we actually show, again, the 2 populations. So nonresponders, slight weight loss, 1.5%. So those people who did really well, the responders, the mean weight loss was 8.4%. And then again, you can see individuals getting up to 12% weight loss. Next slide. And what you can see here is the trajectory, so the nonresponders clearly flat. But you can see the responders here in SRC1 having a trajectory that is continuing down. And we hope when we look at people further out, we will see a continued drop in weight loss in the SRC1 patients. Next slide. When we look at the SH2B1 patients, and this also includes people with the 16p11.2 chromosome deletion, 52.9%, over half the patients, 9 out of 17, achieved more than 5% weight loss within 3 months. The mean weight loss overall, again, about 4%, which includes responders and nonresponders. But again, you're seeing a greater response in responders where we're seeing a mean weight reduction responders of over 7%. So let's look at the box plot on the next slide. The nonresponders, really no change, just staying pretty flat, 0.3%. And again, a separation here where the responders who do well down to 7% and individuals getting over 8%. And when we look at the trajectory on the next slide, you can start seeing clear separations and with some of the nonresponders slightly going up, but the responders, they're doing well continuing to go down. Next slide. So I do want to now go to the Bardet-Biedl patients. So to orientate you to why are we using BMI-Z scores, I want to talk about BMI. So body mass index and you'll may be well familiar with when you go to your doctor for your clinical visit, the body mass index is a way to look at your weight related to your height. So in adults, a healthy body mass index is 25, and you get obese if your body mass index is above 30. And severe obesity in adults that we're looking at is a body mass index above 40. Body mass index is important for children because clearly, if you just looked to weight alone, you would not really see the effect because these children are growing. So people not only look at the body mass index in children, they look at what we call a BMI-Z score. And the Z score relates to standard deviation. So we're looking at individuals who are on the curve. And then the Z score is a standard deviation from normal. And many of the children we're looking at have standard deviations 2 to 3x outside the normal range. So I'm going to orientate you by showing you the BMI-Z scores from our previous cohorts in POMC by allele and LEPR by allele, and then I'll take you to the BMS -- BBS. So this is an individual who'd elect and receptor efficiency, unfortunately, at the age of 2, she is very heavy. Her BMI is over 38. Now a BMI in a child, you've got to be careful saying, well, you're looking at adult's BMI of 40, this is mad math. No, the BMI in children is a lot lower. So if you can see the axis here on the left, that's BMI, and the dark blue line is the middle BMI. And what your normal BMI for a child should be is about 13 or 14. The light blue areas of what we're looking at is standard deviation. So normal is 0. And then if you go above 1, 2, you start going into the light blue. And then when you go above 2 standard deviations, you're really off the chart. You can see this child, unfortunately, is off the chart at age of 2 and clearly has an abnormal BMI-Z score. Next slide. So when we looked at the POMC patients, by allele, there were 6 individuals less than 19 years of age. And the BMI-Z score was above 3. So these individuals had 3 standard deviations outside normal. And on treatment, we saw a reduction in BMI-Z score of about 50%, highly significant clinically and statistically, and these individuals actually started to get back on the chart. So their mean BMI-Z scores were less than 2, getting them back on to the normal chart. Next slide shows the BMI-Z scores in the LEPR by allele patients. So there were fewer patients just to be a number, so a small end. But again, if you look at the mean, the mean BMI-Z score was over 3, 3.52 and if we adjust to 3, which is clinically significant and just meets statistical significance, given the fact the end was small. So next slide shows the BMI-Z score in the BBS patients less than 18 years of age. So the first thing to point out is a number of subjects. So you remember, we had 28 BBS patients who can make up the primary endpoint. They were greater than 12 years of age, 15 were adults, giving 13 BBS patients between 12 and 18. So [indiscernible] is number 16. Well, as you may remember, we did include individuals less than 12 years of age and 3 of them had BBS. So 3 BBS patients less than 12 years of age, plus the 13 BBS adolescents that made up the primary cohort gives you 16 BBS patients less than 18 years of age. The mean BMI-Z score was 3.74. And after a year's treatment, the BMI-Z score came under 3, which is highly clinically significant with a 25% reduction and was also statistically significant. So these children with BBS less than 18 years of age, were clearly benefiting from setmelanotide treatment. Next slide. I do want to come back to the safety results. So as David highlighted, we've now got a large number across our whole program, and we recently did a safety update which we have to do part of our annual process. And we're able to look at all the AEs across the whole program. So as I say, the discontinuation due to AEs across the program is less than 10%. And we're actually seeing why people discontinue. And part of the problem is their skin darkens, and we know that's related to MC1 receptor. And also initially, when people start therapy, they feel a bit sick. So what we're going to see on the next slide is the profile of those parameters. So we've looked at hyperpigmentation, nausea and vomiting, and vomiting. And the x-axis is a bar chart, and the numbers are the number of months. So 1 to 12, a year study -- 1 month. If you look at the hyperpigmentation, you can see that all the adverse events of hyperpigmentation that reported occurred in the first month. So individuals noticed their skin darkening in the first few weeks, and that's where they report the adverse event. What's interesting after that, they don't report it. That's because the hyperpigmentation doesn't worsen. So individuals get hyperpigmentation for the first few weeks and then it stays steady and if they stop the drug, the hyperpigmentation goes away. So what this means is, if we educate people appropriately and say your skin is going to darken, and we can get pictures to give you an idea of how much that darkens, individuals will then go into the study saying, okay, the skin's going to darken. I know what that's going to look like. It's going to be steady. If I don't like that I can stop. So we can manage the discontinuations going forward from the hyperpigmentation. Similarly, when you look at the adverse events of nausea and vomiting, diverse events again occur in the first month. And what we can advise individuals to do coming to the study say you will get a little bit sick in the first few weeks. But once you're on a steady dose, the nausea will resolve, you won't feel sick and you continue on the drug. So we believe as we move ahead, what we've learned from our programs is that we can reduce any discontinuation by education upfront about the fact that you will get hyperpigmentation and you will feel a little sick on starting the study. Next slide. So what I've hopefully shown you with these clinical data is quite remarkable. I think it's clearly we've shown clinical benefit. We're safe and we're clinically effective in those 5 cohorts. We've shown 30% to 50% of patients achieving 5% weight loss in 3 months. We've shown those people who do respond, do very well. In 3 months, weight loss of 10% in heterozygous, 8% in the SRC1 and 7% in SH2B1. And the drug is well tolerated in these populations. Next slide. So the good thing, maybe not so good for the clinical team is because open up lots of work is, we can now move ahead. So what's the 5 cohorts, the plan will be to do a Phase III registration study. So we've shown almost Phase II proof-of-concept data, and the plan is to do a Phase III study with the heterozygous patients, the SRC1 and the SH2B1. We're in dialogue with the FDA, they haven't seen the Phase II data that I've just shown today. We will take that data to them. And therefore, this is a preliminary plan that needs to be refined in conjunction with the FDA. But we already know that they want to see the larger studies and randomization, including placebo. So we're proposing a placebo-controlled study with a 1:1 randomization of going on placebo or going on to setmelanotide and we used the dose titrations we've done before, 2 to 3 for adults and lower for younger children. And then we'll look at maybe up to 200 patients. So we'll have a decent number of patients reach cohort. And will stratify based on their genes and on their variants. So we'll make sure we'll include different variants within this. The primary endpoint will be at 6 months but we'll also be following patients for a year to ensure we've got a year's worth of data. And we hope to be able to transfer the placebo patients on to active therapy. So some of the endpoints we're considering are mean change in weight versus placebo, but we also want to look at responder versus placebo. So our prediction would be that we will show a greater than 10% weight loss in the treated group, but we won't show that response in the placebo. So we'll be able to show a separation between the responders at 10% and 5% in the setmelanotide compared to placebo. So we'll be looking at a number of endpoints, responders, mean weight loss. And we'll also be looking at BMI-Z scores in children. Next slide. Now I want to also touch on another study we're going to do. So you'll hear from Al later, that in addition to the 5 genes I've talked about today, with data, we believe scientifically, there are well over 30 genes that may be responsive to setmelanotide treatment. So we want to combine our knowledge of our Basket Study with an extension study. And using the same approach, we will take individual who -- the phenotype of early onset severe obesity. We will take people who've got a gene defect in the pathway, and we look at them a trial, the third step is a trial of treatment. We know not everyone will respond. So if they don't respond in 3 months, they will stop therapy. But if they do respond to show more than 5% weight loss, we have an opportunity to do what's called a randomized withdrawal study, where we'll randomize them to active therapy of placebo. We would predict that those people who are on active therapy will continue to lose weight and get over 10% weight loss. And if they're randomized to placebo, they will then gain weight, and then we will build to rescue them. So this allows us to do an open-label upfront study of the new genes with a Phase II, Phase III going into randomized withdrawal, if we look at the responders. And again, we'll be discussing these designs with the FDA. Next slide. So what does 2021 look like from a clinical trial perspective? So we've shown you 5 cohorts from the Basket Study. It's worth noting that we have other cohorts coming through and we've got the MC4 rest of the cohort. So we've looked at individuals who've got a defect in the receptor of cell and believe are potentially treated with setmelanotide, we'll have that data towards the middle of the year and we'll be able to share with you. We also decided to look at individuals who've got a defect in the hypothalamus due to craniopharyngiomas. So we know these individuals following surgery for their craniopharyngiomas are deficient in hormones. And they also gain weight, which means we think they're deficient in the signaling in the MC4 pathway. And therefore, it's the potential was setmelanotide to treat individuals who have hypothalamic obesity due to craniopharyngiomas. And we're going to start a Phase II study in this population in the first half of this year. Towards the end of the year, we hope to get up these clinical trials up and running. So the 2 pathway studies, the one looking at the cohorts we just decide and another one which will look at the new genes. Given we're looking at individuals through early onset obesity, we've got a label that allows us to go to 6. We want to go below 6 years of age. So we're going to look at pediatric patients with POMC, with BBS, and we're going to do a specific pediatric study in 2 to 6-year olds. And thinking further ahead to the future, last year, you saw our data on weekly in generally obese, showing that weekly formulation was effective and safe. We want to do a weekly study in our rare genetic disorders of obesity. So we'll start some registrational work towards the second half of this year. So plenty to do in the clinical trials in this exciting time. And hopefully, you're excited as I am about seeing the data and the progress we're making with clinical work with setmelanotide. And with that, I'll hand over to Al.

Thanks, Murray. Good morning, everybody. So it's been about 18 months or so since I stood here and introduced you to a new clutch of indications that Murray's just walked you through. I'm kind of espoused, as is my want, on the power and the potential of the pathway. But I think the clinical data that Murray just delivered kind of talks for itself in both of those regards. So what I'm going to do instead is move on to talk to you a little bit about some of the underlying concepts that you've heard about today. And how they support our understanding of the definition of an MC4 receptor pathway genotype and how that translate ultimately into a projected patient population in the 5 cohorts Murray just introduced to you, but also how we're going to pull that learning through to define a much bigger opportunity, the much more exciting opportunity of the 31 genes in this expanded Basket Study. So clinical data is fantastic, no doubt. But from my viewpoint, I think the most exciting thing really is the validation of the scientific strategy and the confidence that, that brings us as we move forward. So you've heard this from me before, but each indication that we bring forward to you is defined by the dysfunction of a gene. And it is only ever going to be as successful as the evidence that ties that gene to the MC4 receptor pathway and to human obesity. So I think our Phase III success is POMC, PCSK and leptin receptor via relay deficiency obesity, recent data on BBS and now this proof-of-concept data really all points to the fact that our underlying approach to the rationalized selection of genes in the MC4 receptor pathway who might benefit from setmelanotide is working. So next slide, please, Dave. So as you can see here, listen, these are the indications that we've been working on today and to the point that I just made, each one has very strong rationale for its involvement in the pathway. And as David spoke to, there's a clear and strong mechanism and justification for the MC4 receptor pathway in the regulation of body weight. And as we move forward with our clinical data, you can see that setmelanotide, time and time again, seems to be proving out our scientific hypothesis. Next slide, please, Dave. But more than the successes, I think the other thing that we've garnered for work over the last few years is knowledge. Now our clinical data continues to support the fact that setmelanotide offers significant clinical benefit in individuals for whom a decrease in MC4 receptor pathway tone is a contributing factor to their severe obesity. So essentially, we continue to believe that an individual's underlying genetic pathophysiology is a necessary factor in the clinical benefit that we observe. But as we've learned from our data, as Murray has just shown you, while necessary, an MC4 receptor pathway genotype may not always be sufficient to be able to predict a response. And that is because of the inherent complexity of the biology that underlies body weight regulation. The number is easily defined, a BMI, a weight. But the concepts, the reasons beneath that number are a lot more complicated. So while kind of defining the aspects of step 1 and step 3 of this 3-step process that Murray and David have both introduced, you have relatively easily measured and understood, it is step 2, this genotype notion that is the biggest scientific challenge but one, as Rhythm's core competency, I think we're in a really good position to be able to address. So over the next few slides, what I'm going to do is kind of just walk you through the 2 steps of this. What defines an MC4 receptor pathway genotype. At the first level, we have the gene and at the second level, we have the variant. Now in both paces, Rhythm is leveraging very well established, published scientific frameworks that help inform our interpretation and selection of both indications by gene and patients by variants. Now our understanding is growing. That's not just through Rhythm's own research, the academic world is stepping up to this as well as it has done over the last 20 years. But also, and most importantly, by virtue of the learning that we get from the deployment or the use of setmelanotide in these patient populations. That's a unique thing that only Rhythm can bring. Now all of this is great combination percentage. It changed the way in which obesity is viewed and is ultimately treated by stratifying by these rationalized genetic subpopulations. But all of that research and all of that change can only begin with one foundational requirement, and that is genetic testing. DNA sequence data really is Rhythm and this community's lifeblood. So next slide, please. Now when last we met, Rhythm had sequence approximately 13,000 severely obese individuals. In little under 18 months, we nearly tripled the size of our genetic obesity database to approximately 37,500 individuals. Now from my standpoint, I really do not think that the power of this resource can be overstated. It subserves so much of what it is that Rhythm is about and trying to achieve. From a research side, this is one of the largest known databases of its kind, and it is certainly the largest focus on the genetics of the MC4 receptor pathway. It really is the jewel in Rhythm's scientific crown. It forms the basis of all of the gene and all of the variant research I'm going to touch on today and helps us as we move forward in identifying new indications with new populations who may be able to benefit from setmelanotide. But beyond that, it's also helping to identify patients. And in doing so, it's bringing awareness to these rare genetic diseases of obesity is helping to build the communities, and it's driving medical action in these populations. Now the large number of sequences you can see here are derived from 3 unique but complementary streams. And we deliberately designed them that way to help deliver on the core components of Rhythm's mission, as I've just laid out are on the side of the screen. So our uncovering rare obesity sponsored genetic test is a diagnostic community tool that's available to physicians who are suspicious of a potential underlying genetic cause to their patient's obesity. And it really has been critical in helping us bring awareness of these rare diseases to the patient and to the physician communities. Now GO-ID, that was Rhythm's clinical genotyping study. That's really where it all began. And that was instrumental in getting this database off the ground and identifying patients for our initial clinical trials. And it did that by delivering on 9,000 DNA sequences from individuals with early onset obesity and hyperphagia. And finally, we have our bio-banking initiative, which is a global network of collaborations with obesity researchers, with treaters, with even the biggest institutes that generates very large quantities of DNA sequence data to help us rapidly accelerate our internal research into the pathway and identify a lot of the new indications that I'm going to talk to you about in a few slides' time. So in case I didn't state it clearly enough at the beginning, I really don't think that this obesity -- this genetic obesity database and the power of it can be overstated. So next slide, please. Now as is the scientist's want, with data comes knowledge and with knowledge comes growth. And for those of you who were with us in 2019, you'll recall that as part of the introduction to SRC1 and SH2B1 deficiency obesities, we presented a predictive approach to our patient selection. And from that, the derivation of our prevalence estimates, and that was based on very well-established industry standard computational tools to help inform a priority our variant classification. Since then, we have learned a lot. It is -- comes from what we've garnered from the genetic obesity database that I've just talked to you about, from the clinical trial data on our real-world experiences of setmelanotide that David -- that Murray has just introduced you to, and also for the approval of IMCIVREE for POMC, PCSK1, leptin receptor deficiency obesity. So within the context of the genes that we introduced you in 2019 and that Murray shown you clinical data for now, I want to talk just a little bit about these real-world experiences and how they've changed our variant classification approach. So Murray has already touched on this but Rhythm is now moving forward with an established set of variant classification guidelines from the American College of Medical Genetics, ACMG, the experts in this particular space. And they put these out in 2015 to help standardize the way in which DNA sequence data is interpreted by medical genetics across the country and actually adopted around most of the world. And that really is because technology outstripped scientific advance in the fact that we were able to generate large quantities of sequence data, but the art of trying to interpret what you're seeing is always lagging that little bit behind. So this is a perpetuity evolving science, evolving on the part of Rhythm's research, evolving on the part of the research of all of the academics and all the diagnostic labs out in the world. But these are the industry standard for the diagnostic labs across the country. So conceptually, this approach leverages the same underlying scientific principles that we used in 2019 is just now rolled up into a far more broadly accepted and established framework. So next slide, please. Now in essence, these guidelines basically use the cumulative burden of scientific and clinical data to derive a probabilistic determination that a variant is likely to be contributing to the disease within the context that you're looking at it. So for us, it's going to be severe early onset obesity. Now in doing that, as Murray has kind of already touched on, any variant, it could be classified into 1 of 5 states: Benign and likely benign on the bottom left here, pathogenic and likely pathogenic at the top, and then this large swath in the middle called the variant of uncertain significance. Now I don't think the benign and likely benign needs a lot of explanation nor pathogenic or likely pathogenic. But I do want to just take a little bit of time to orientate you around the boost. Because as you can see illustrated here, they really do represent the preponderance of variance in our genes, but also across all genes in the genome. And that is by virtue of the fact that there just isn't enough scientific data at hand right now to be able to pie and there's either being likely benign and benign or likely pathogenic and pathogenic. So essentially, the boost is when all is said and done, when all knowledge comes to bear and scientific research is complete, will finally be clarified as either being one or the other. And at the moment, they remain in this ambiguous world of the variant of uncertain significance. Now by virtue of the fact there are a large number of these variants is probably unsurprising that they're highly represented within our database. And by definition, they also have the greatest uncertainty of response because we're not 100% sure of their contribution to pathway deficit. Murray has already shown you clinical data that supports exactly that logic. Now previously, we had tried to use a solely scientific approach to clarify apriority, which variants represented the hidden likely pathogenic or pathogenic and to move those patients board within our clinical program. But the clinical data that Murray has shown you shows really clearly that 12 to 16 weeks of setmelanotide therapy is the best bio asset for being able to identify patients who are going to benefit long-term from setmelanotide therapy. So as such, we just don't believe any longer that a paucity of scientific data should be a barrier to those boost patients who could benefit from setmelanotide. And as a result, we propose to include them moving forward in our clinical program. Now rest assured, dovetailed with this real-time clinical approach, our internal translational efforts are trying to prospectively clarify these variants through functional biochemistry through genetic epidemiology to kind of separate the water from the wine. And in doing so, we believe it will become ever more efficient and ever more successful at picking individuals most likely to respond to setmelanotide. So I know I may be labored this slide a little bit, but I think this is really important. So the take homes on the boost really are. There are lots of done, right? That is by virtue of just the deficit and the scientific knowledge that will all the community are working towards and try and reconcile. They represent the largest population and the one where the response is most uncertain. And we are working through setmelanotide and through our internal research efforts to try and clarify them to be able to move them forward in our clinical program. Next slide please, Dave. Now importantly, all of this learning about response and about variant classification can be pulled through to help us interpret the potential addressable patient population in each one of these rare genetic diseases of obesity. Now as a result, we have refined our prevalence estimations for 2019 that reflect this new real-world understanding of the rate of clinical response by variant class and also to capture this now much broader boost population. So we've moved away from the scientific apriority estimations to real-world predictions. What you can see here is that on a by indication basis, we've greatly increased the opportunity in POMC, PCSK 1 and leptin receptor heterozygous and remained relative consistent from our 2019 numbers in SH2B1 and SRC1 deficiency obesity. Now the contrasting directionality here speaks to exactly what I said on the previous slide, which is just the depth of scientific data that is available to inform the classifications of the variance across the 5 genes. We know a lot more about POMC, PCSK1 and leptin receptor than we do SH2B1 and SRC1. That's because Rhythm has been working on them longer and because the academic community has been working on them longer. Now the more science we bring, the more clinical data we bring, the better we will be in clarifying the boost population in SRC1 and SH2B1, give us more confidence in our responder predictions and be able to adjust our projected populations accordingly. So next slide, please, Dave. So in sum, literally in sum, these indications -- across these indications, they lead us to believe that the total addressable patient population across the 5 genes could exceed 100,000 people, between 100,000 and 200,000. So let me just walk you through the 3-step process of how we got to these numbers. So first and foremost, we have the phenotype, as Murray has explained it to you, early onset severe obesity. Based on U.S. centers data published in 2018, there's an estimated 5 million individuals in the United States of America who present with early onset severe obesity. Now taking real-world data from our DNA sequencing database that reflects this exact population, we find that approximately 10% of individuals carry either a pathogenic, a likely pathogenic or a variant of uncertain significance in 1 of the 5 genes. In addition, there's a 5% of individuals who carry the very interesting PCSK 1 variant N221D, which makes up this additional 5%, bringing our total to 10% to 15% of individuals with early onset severe obesity who have an MC4 receptor pathway relevant genotype. And then finally, we take a cut for the observed clinical response based on our learnings from the Basket Study. And what that gives us is a 40% response rate in pathogenic and likely pathogen variant carriers and a 20% response rate in individuals carrying a variant of uncertain significance. And that's derived from real world experience. So we believe what that leads us to is an estimated addressable patient population of between 100,000 and 200,000 individuals in the U.S. Next slide, please, David. So that was the variant level. I know confusingly, I said that there was gene and then there's variant. We've kind of started at the variant on the -- within the context of genes you're already familiar with. Now I want to come up a level and just talk to you a little bit about how we pick our genes in the first place. The 5 genes for which we've already shown you proof-of-concept data. And now moving on to this 31 new genes that both Murray and David have alluded to. So as I said at the top of the show, obese data really do build our confidence in the underlying scientific strategy that we're using to pick mechanistically rationalized within the context of setmelanotide as an MC4 receptor agonist, these genetic subpopulations who could benefit from that sort of -- from setmelanotide therapy. We know how to pick them essentially. So our internal methodology for the selection of these genes is not something we've really given likes to before. It's something we've been working on and honing over the last 3 years. But now that we're moving towards this much larger multi gene-based indication and thus larger cumulative patient populations, I think it seems appropriate to give you a little bit of a peek behind the curtain. So if we move to the next slide, I'll outline exactly how it is that we do what we do. So our approach to gene selection is based on the core principles of the very well accepted ClinGen gene disease clinical validity framework, which was a paper published back in 2017. And we overlay that framework with our own internal expertise on the MC4 receptor pathway and all of the specific scientific nuances that are going to help tune it towards our end, which is to try and identify individuals who are going to respond to setmelanotide. Now much like ACMG classifications, our approach utilizes again the cumulative burden or the amount of available data, both scientific and clinical data to help rank these genes into confidence-based tiers. And it reflects the strength of the association to the MC4 sets pathway. Now I'm not going to bore you with the gory scientific details, but suffice it to say, we capture as much relevant data as we can from the external published literature and from our own internal research to basically inform this process. Everything from where is the gene express. Well, the MC4 receptor pathway is in the hype we want to see that the gene is expressed in a hypothalamus, all the way through to what is its function in the pathway. What happens when we remove the gene from a mouse? Does it lead to an obese mouse? That's a pretty good sign. And then finally, through to what is the association of that gene with human body weight. Now all of these data points basically sum together to create an internal scoring rubric, the rank orders these genes from weak to very strong with the responsive category right at the end here in the magenta reserve for those genes that have demonstrated clinical proof-of-concept with setmelanotide. So next slide, please Dave. So most importantly, I think, for us, is really heartening is that the principles of these frameworks forms the basis of our selection of genes to date. All of the ones that you can see listed here that have either been through our Phase II or our Phase III studies. And all of them, with the exception of ALMS1, which is the Alström's gene were classified as strong or very strong by this methodology and for which we have now demonstrated positive clinical data. So while in genetics, there is always more to learn. And this certainly lends credence to our approach and builds confidence that the genes reaching the same level within this approach of strong and very strong, represent the next best set of genes for Rhythm to evaluate as rationalized subpopulations who would benefit from a precision MC4 receptor agonist therapy such as setmelanotide. Next slide. So to that end and through Rhythm's internal translational research efforts, we have collected and curated an initial list of 113 genes with potential ties to the MC4 receptor pathway. I don't believe that this is all said and done, right? Rhythm's internal discovery work, plus the work of our academic brethren is going to add more and more genes to this list. But our initial set is 113. Now running this through our gene prioritization methodology, we're able to now rank order them based on their -- the strength of their association to the pathway. And in doing so, we define their next step within our development program. So as Murray has already detailed the 5 responsive genes, POMC, PCSK1, leptin receptor, SRC1 and SH2B1, for which we presented positive clinical data today, they're going to be form the basis of our next Phase III study. 5 very strong classified genes and 26 strongly classified genes will form the basis of our new expanded Basket Study. That's the 31 genes that Murray and David have both alluded to. The remainder of this list represents opportunity for focused nonclinical research that is designed to clarify the potential of either these weak or these moderate genes in such a way that may elevate them to the strong and very strong with further scientific data. Just like with the ACMG, I fundamentally believe that a lot of these genes are classified in this way, not because they're generally weakly associated with the pathway, we just don't know enough from the science to be able to say that they're strongly associated yet. So we will be working hard both on these genes and to continue to populate our master gene list and bring new indications forward. So while the signs remain strong and clear, as David said. And my personal confidence in the defeating the [indiscernible] hypothesis is -- remains high. Ultimately, it is setmelanotide has that perfect bioassay and time that is going to guide us to an understanding of the true opportunity that exists in this expanded approach. Next slides, please Dave. So in sum, we have learned a lot, which is the name of the game in my book. And learning is paramount for keeping this at the leading edge of how genetic diseases of obesity are understood, how they're diagnosed, and ultimately, if you can rationalize the targeted therapy, how they're treated. So just to take you through the highlights, our Phase II basket data has validated, in my mind, in combination with our Phase III data, our gene selection methodology. The expansion of our DNA sequencing database is absolutely critical to driving forward our agenda, both in terms of research, identifying patients and building the community. And our recent understanding of clinical response has just made us better at being able to predict we believe our potential addressable patient population is. And finally, that all of these achievements and all of this learning have highlighted to us that a much more meaningful opportunity exists to address the medical needs of an underserved population through the advancement of our new and expanded Basket Study, which now includes 31 new genes. And with that, I'm going to hand it back over to David.

Thank you, Al. So in concluding here, on the next slide, one, I'll just remind you that we are fortunate and pleased to have an approved drug, IMCIVREE, and look forward to providing updates as we go through here, go through the rest of the year. Obviously, looking forward to our first commercial patient in the first quarter. Next slide. You've heard from Murray, a very detailed and long list of activities, milestones that we look forward to in the upcoming year for which we truly believe will be a transformational year for Rhythm. So you've heard the first two, the proof-of-concept data and the update to the genetic sequencing. First commercial available patient. We'll be initiating the Phase II trial for hypothalamic obesity, which we haven't talked about much, but which is, I think, an exciting opportunity and just a natural extension of the science. We're just following the science here. I'm approached by one of the thought leaders in the field who said this certainly seems like a very reasonable place where, in fact, those with their intact MC4R receptor following surgery for craniopharyngiomas might impact benefit. We'll have initial data from the Phase II Basket Study on our MC4 rescuable population, again, another cohort like the ones we presented today. And then we'll have a full data analysis from the pivotal Phase III released in December for both Bardet-Biedl and Alström's. And I expect that will be released at an upcoming meeting. In the second half, we expect to hear from the EU on our filing around POMC, PCSK1 and LEPR. We'll have regulatory submissions, filings for the BBS, Alström's to be decided. We'll have our initial trial in pediatric patients aged 2 to 6, critical activity, genetic disease starts at birth. We know from Bardet-Biedl that some of the most pronounced weight gain happens between 2 and 5 years of age. And obviously, intervening early perhaps gives us a chance to change the overall trajectory there. We have the initial pivotal MC4 pathway trial in the HET in the exploratory trial for these 31 genes, and we'll initiate a registration for the weekly formulation. So a big year, lots to do. Next slide. So today, in the last slide, and then we'll move to Q&A. You've heard as we started the day, the largest data set that Rhythm's ever released in terms of 5 cohorts, 65 patients in total, achieved the proof-of-concept in all 5 genes. We've unlocked what we believe is an estimated target population for the U.S.-only across these genes. And again, the numbers outside the U.S. should be comparable or larger of 100,000 to 200,000 individuals. It's the largest known genetic obesity database, approximately 37,500. And we believe that database and Al's interpretation of it, support our approach to gene selection and variant classification. And I really hope again that what -- it's not so obvious, this whole ACMG classification, the divisions between pathogenic, likely pathogenic and VUS. And I -- maybe one key take-home is that failure of a VUS patient, a patient with a genetic defect, that's classified as VUS to respond, does not necessarily mean the drug did not work in that individual, but more likely indicates that, that VUS genetic defect was not tied to a reduction in tone in the pathway or there were other compensatory factors, right, that blinded it. So again, we think it's just a big cohort that this clinical bioassay is going to help us in a very precise way sort out. And finally, there's a very clear pathway forward. And we've described 2 trials and in active dialogue with the FDA to finalize those trials, so we can get started. And with that, I'll turn it over back to the operator, and we'll open it up for Q&A. I believe Dave is going to read the questions for us. And I'll provide any additional instructions if we need.

Yes, great. Thank you, David. I'm going to stop to share and ask you and Murray and Al and Hunter to turn your cameras on. And we'll start with the first question from Phil Nadeau at Cowen & Company. Can you discuss the rationale for analyzing only the completers and analyzing the weight loss data? The second follow-up question is when the FDA analyzes this Phase -- your Phase III data, will the responder rate and mean weight loss be calculated only for completers or will the FDA use an intent-to-treat analysis?

Yes, thank you. Murray, do you want to take that?

Yes. So the heterozygous cohort was an intent-to-treat. So the 35 patients there were intent-to-treat. The reason we presented completers in the SRC1, SH2B1, is -- by definition, there is an ongoing study, and we've actually not got at least 12 patients who have continued. So they didn't have values that were there. So we did look at that. But yes, we'd expect to be able to look at the intent-to-treat. And I think it'll be consistent with the HET. So the rationale was early data, and we didn't want to show data on people who've got 4 weeks and say they're a nonresponder, when clearly, they haven't had enough exposure. So I think this is more about where we were in the study design rather than the not doing the intent-to-treat.

And maybe just to add a bit, again, it's a good question. 2 sets of data there. One are the individuals who dropped out. Second are the individuals who are still ongoing. Obviously, there could be a mix of responders and those who are ongoing. If you counted all of those who dropped out as, in fact, nonresponders, they will pull down the numbers a bit. From a pure regulatory standpoint, the -- this is a Phase II trial. And so again, we've looked at that calculation in sort of a worst-case scenario and it's robustly -- the conclusion robustly stands here. So the ability to move forward to Phase III based on proof-of-concept having been demonstrated here will be unaffected by that part of the analysis. So whether they -- we'll present all the data to them, and of course, have that as part of the discussion. Next question?

Great. Okay our next question, we have a list of questions from Derek Archila at Stifel. Team, congratulations on the data. Questions from the Stifel team. First, how many HET, SH2B1 and SRC1 patients have been identified to date? Two, where are you in the discussion with the FDA on the Phase III basket approach and how amenable do you think they will be to this approach? Third, how long do you think it will take to enroll a Phase III Basket Study and how large a study could that be when -- and when can we expect data? Fourth, on -- actually, why don't we leave it there and I'll come back to the last 2 since they're relatively separate?

Yes. So maybe on the first one, just in terms of roughly number of patients. Al, do you want to take that? Can you...

Yes. So our numbers remain pretty consistent with -- in terms of yield that we demonstrated in 2019. It's one of the very nice things about the way in which the database -- the expansion of the database has performed. So consistently, our yields remained in the phenotype and genotype [indiscernible] taking responder car remained in the 2% or so range. Number of patients continues to increase within our database. We've made significant advances from 2019, where I think the numbers were in the order of about 250 to 300 but we continue to identify more at a pretty consistent clip.

The one thing I would add to Al's comment for Derek is that most of the new sequencing we're doing today is through our URO program. And our URO program is submitted directly by the patient's health care provider. So that provides a very direct link to patient underlying the genetic sequence that we receive, and therefore, is a much faster route to identification than, for example, the work we did with GO-ID or with a biobank, where the patient may be somewhat removed from the original submission to the biobank.

And Dave, the second question, we had about 3 questions, I think, on the upcoming clinical trial. I missed the second question.

It's about the discussions with the FDA, where are we in those discussions? And how amenable do you think they're going to be to the approach?

Yes. And then how long will it take us to format when [indiscernible]. So Murray?

Yes. So we are in discussion. We've had one meeting just before the end of the year where we didn't share the data that we discussed in principle. And the -- we're comfortable with the principle that we shouldn't be doing 1 gene at a time. In other words, that would increase 1 gene, 2 genes. They got the principle that we should be looking at the pathway. I think the relies the population is bigger. And therefore, the set is bigger, we really want a placebo-controlled study rather than just what you do in very rare disease where you just do against baseline. So as I said, we want to come with a placebo-controlled type design, they actually did like randomized control, but said, just not from its own. That's good data that we do with placebo. So we think we're making strides. We'll go back with them the first half of the year with the data. This is sort of end of Phase II, we can say here's the data, here's our plans. And we hope then to get going by the end of the year. I think it will take about a year to recruit. If you have to do a year's study, it will be another year, so add up a sort of a year, recruitment, another year, and we're sort of 2024 -- 2023, '24.

Next question.

Thank you, Murray. When you think about enrolling -- and I'm going to split this up into 2 as well. When you think about enrolling the Phase III basket, how will you control for over enrollment of nonpathogenic or VUS variants?

Yes. So that's a very good question. So you can stratify. So it's complicated that you can't stratify. So we stratify -- and normally you stratify by age and body mass index. In this case, we stratify by gene. So we'll take the people who've got the gene defect. And as Al said, there are a lot of VUSs. So the last thing we want to do is have 20 people with 1 gene and they're all VUSs. So we need to make sure that we stratify according to the ACMG classification. And as our scientific knowledge increases, we hopefully would do people who were benign, throw those people out because we know they're not to respond. So the ideal stratification is to get people more likely to respond, which would be the more pathogenic. So we do want to load up the study with less likely responders.

And just to add to that, in the meantime, our internal research is constantly generating data that is going to help clarify the VUSs who are more likely to be pathogenic, likely pathogenic, before we hopefully get to the point of actually enrolling first patients. So it's -- there's more to bring to help in the process.

Great. Thank you, Al and Murray. And then Derek's last question. On the commercial, look, you're now at approximately 20x your total addressable market, how are you thinking about pricing in the future?

Yes. Well, as people know, we have priced the current therapy IMCIVREE in recognition of the -- both the approved population and the potential approval in the Bardet-Biedl and Alström's syndrome. So that is a price that would not change through that course of activity -- series of activities. These populations, of course, some, they are, in fact, much larger this is a -- as I highlighted in my introduction, this is an area, a group of individuals who suffer from many of the features of a classic rare disease population. And so there's a lot of work to do to identify these patients and help create a system that is capable of identifying and caring for them. So it won't be that overnight, we go from 5,000 to 100,000 to 200,000 individuals who are lined up looking for the drug and the impact on the system, accordingly large. So again, we'll make that decision. We have the ability much easier to go down in price. I am very eager, to be honest with you, to reduce the price. If, in fact, the volume supports it, but we're under no pressure to do so. We'll evaluate that, of course, as we go forward.

Thank you, David. Moving on to a few questions from David Lebowitz of Morgan Stanley. With respect to the overall members cited for each group as potential addressable U.S. patients, Slide 65, are these numbers considered to be potential responders based on the data observed or is that the number that could potentially try the therapy with each mutation with some being responders -- with only some being responders. Sorry there was a typo.

So just to clarify, the number we're referring to is the 100,000 to 200,000?

I believe so, yes.

Yes. So that is, in fact, the responder cut. So if you remember, again, from that slide, Al's 5 million starting population, which are all of those individuals, U.S.-only, who have early onset severe obesity, 10% to 15%, 500,000 to 750,000 might be expected to have a genetic defect consistent with 1 of those genes. And of that group, applying the responder rates different rates for pathogenic and likely pathogenic, higher potential response rates and VUSs or lower potential response rates where that as an overall group, gets you to the 100,000 to 200,000 responder population.

Thank you. And just one more question from David. He did have a few questions about the trial and the timing and the FDA discussions which we already addressed. But his last question is, given all the mutations that you have identified, how do you intend to raise awareness with the physician community, given that they have limited exposure to those points?

Yes. That is the challenge. And again, the good news about these individual indications is that they share a common presentation, and they are likely to see a common group of physicians and the test required to identify them is the same test. So the URO process that Al talked about, which is currently being expanded to include the new genes, some of the 31 that we will be studying in this exploratory expanded basket trial are in our current test. There are additional genes to add up to the full 31, which will be added to the test. But the goal here is to have 1 test that allows a physician health care provider who sees a patient with early onset obesity, thinks about potential genetics to screen and identify, again, a potential 1 of 36 different genetic outcomes there that might make them eligible for the trial. We will be very focused on anchoring our community development efforts around this clinical trial. So you can imagine a clinical trial effort between the 2 trials of this size involving 50 to 100 sites globally. At each one of those sites will be an area where we will concentrate our screening efforts so that patients who are identified will have a call to action, if you will, and actionable, they could be enrolled in the trial. There'll be a small percentage early on who might be eligible for a commercially approved product, IMCIVREE. But the concentration of our screening efforts will be around these clinical trial sites and then some satellite sites around each clinical trial site. So that's how we envision building the community, and the community will support the commercial efforts here. And one last thing, when you have an area in a rare genetic disease for which there has been nothing, I mean, classically, why test? What's the point of testing? There's nothing to do. I'm not going to change my care plan. Whereas now we have demonstrated and increasingly are demonstrated -- demonstrating across these genes, now, there's something to do. Medically, you should do this. You need to do this. So it will ramp, but there is a ramp associated with it.

Great. Thank you, David. Now moving on to Michael Higgins at Ladenburg. Relative to the basket study in sequencing, how long did it take you to get the 37,500 sequences? And as a follow-up, how long will it take us -- take you to get to 100,000 or even, say, 1 million and could you talk a little bit about the costs on reaching those numbers?

Yes. So I'm going to ask maybe Al and Murray can both jump in here. I think it's not quite the right question about how long it took us to get here because we didn't start focusing our screening efforts from day 1. I mean, that's been a very recent over the past 2 to 3 years, I guess, in a sense, that's the answer. As you heard from Al, that 37,000 included 2 to 3 different sources of information, one of which is the biobanks, which is not the way, of course, we will be focused, going forward. It's not to say we won't use biobanks. The ability to screen widely is basically an investment question. Our goal will be to screen enough individuals in the next 2 years to fill these trials. That's going to be the minimal goal. And to give you a number that we might target, that might be, again, depending where we end up with the FDA and the like, anywhere between 10,000 and 20,000 individuals we would look to have sequence to identify enough patients to enroll these trials. Beyond that, of course, the more you can sequence, the better. I mean -- and so again, that's a little bit back to what we can afford and what we can support outside this clinical effort. The cost of these screens right now are on the order of $400, $500 per test. So it's not an insignificant investment, but also we fully expect as to our partners that as the volume of screening increases, the cost of the individual screens will go down.

Yes. Maybe I can add. So if you look historically back, it took ages to get initial studies going. But for SH2B1, the physicians, the basket sites recruiting, they're already doing testing to see if they're suitable for one team. And then when we went to look back, they went and said, oh, I've got lots of SH2B1 people. So they were able to come in. So the more genes you look at is more efficient because of the physician who is testing, they don't know what the genetic defect is in their patient, they just know the phenotype. You do the test, you find the gene. So actually we'll be able to do -- that's why the beauty of the exploratory study allows us to do things in parallel.

I'm sorry, not to add too much here, but I came out of a world in Genzyme, where we were screening for, as many of you know, rare genetic diseases. These lysosomal storage diseases with frequencies in the order of 1% or less in some instances. That rate -- that hit rate, if you're encouraging a group of physicians to screen and they have to send 100 tests to get 1 positive. They send their first 20 and they're 0 for 20, they stopped screening. We're in a world now where the number of genes as you've heard, gets us a hit rate, which says, if you seriously are looking at your patients with early onset obesity, every physician is going to have a positive test. And when you get a positive test, it reinforces the fact that screening makes a difference, and then you begin to ramp.

Great. Thank you. And Michael's last question is, for the pivotal trials, have we worked out specific numbers needed and how that could affect time to enrollment. For example, he asked POMC could be 10 patients, but VUS has a lower responder rate. So I don't know how we can address that.

Murray, do you want to take that?

Yes. No, that's quite a difficult question to answer. So we are looking at all the different powers, but we do believe you may need about 100 patients. So we've got to look at -- we may not be trying to show a power difference for each of it. We look at it 1 gene versus placebo or the group versus placebo rather than try and show a statistical difference for each variant. Otherwise, that would be complicated.

Great. Thank you, Murray. And then the last set of questions comes from Graig Suvannavejh at Goldman Sachs. Let me just looking through his numbers. The first question we answered on the potential addressable -- on the number of potentially addressable patients and patients identified. Second question is of the 37,500 tested, what percentage are homozygous, HET, SRC1, SH2B1, N221D? And how many are appropriate for setmelanotide?

So I'm going to assume that question means how many are appropriate for setmelanotide today, i.e., the IMCIVREE label, which I would remind people is limited to the POMC, LEPR, PCSK1, while the [indiscernible] homozygote population. Al, do you want to comment on the frequency? What's our expected hit rate for that?

Yes. So for SRC1, SH2B1, the frequency of the biohelix is fleetingly rare in the orders we see with POMC, PCSK 1 and leptin receptor. So the focus, again, is on the heterozygotes, the yield in our POMC, PCSK 1, leptin receptor, heterozygous remains consistent with what we've seen before. So the homozygous and the compound HET are very, very rare across these 5 indications.

This is -- back to Graig's question, this is back to why I've been clear. We'll continue to be clear. The expected number of patients, again, for IMCIVREE with our initial approval and indication, it is about validation. The number of patients in the first 1 to 2 years is going to be in the 10s. The number of patients we know today between clinical trial patients and the like is, again, in the 10s, so clinical trial in outside clinical trial. And we will find these patients, which is why, again, our effort, not putting a sales force on the field in the field looking for these patients, specifically because not a good use of time or money. These patients, they will come as we begin to screen more globally, both geographically and conceptually, this early onset patient population. And looking for these other genes, we will find at a low frequency in the POMC, LEPR, PCSK1 homozygote population.

Great. Thank you. Question, looking at the Phase II data, were there any differences in the data related to male versus female?

We've looked at whether there's any difference between male, female or anything to say why someone responds. So the body mass indexes were similar to nonresponders and responders, no difference in set response. And actually something that I probably should have said in the presentation as well, we did look at the 3 genes and see if there's any difference in the 3 genes and there wasn't.

Thank you, Murray. For the new Phase III, what are you expecting to see from the placebo treated patients?

Yes. So in some sense, from the true placebo who in the trial design, do grant, we expect the weight to stay flat. And what's interesting is in the COVID world, actually, people have put on weight so depending on where we are with cover world, I think most placebo patients will probably stay flat or maybe increase. Now people are concerned about placebo effect. The reason I'm comfortable with the data we've got without placebo is given COVID and given the population we're looking at who are obese and severely hungry, you really don't expect -- they've already tried all the diets and exercise, so you get very little placebo response in the population we're looking at. So in the Phase III trial, I expect no response in placebo. And that's why I think even though it may be diluted by nonresponders, there'll be enough responders that will show a separation against placebo.

I mean, if you look at the non responder population and the data that Murray showed you, in essence, they were getting a placebo, right? It wasn't working on their pathway in the sense that the pathway wasn't reduced in a way that would cause it to benefit, and they had very little change. So I think we have a fair amount of confidence that nothing -- the placebo group will not have a very significant placebo effect. And the second thing to remind you, and I didn't focus on that when I flashed the slide up, I'm going back to our original Phase III studies. In that design, we had a 2-week placebo -- randomized placebo withdrawal period. And for both the POMC and the LEPR, it was quite striking in the sense that the hunger came back immediately. And in a short 2-week period, both groups gained on the order of 5 kilos. So there was a very rapid return. The sensitivity of hunger than the accompanying weight loss to the drug is real. So I think, as Murray said, we're pretty confident they will separate. The other endpoint we would ask for, maybe as a secondary, all to be negotiated, is a separate analysis, which would allow us to look at the responder group versus placebo. And of course, that would be quite powerful.

Great. And then Graig's last 2 questions. First, what is needed to advance Alström's syndrome? And when may we provide an update? And his last question is, we've adjusted to some degree on IMCIVREE, how many patients have been treated thus far for commercial? And what is the expected cadence or uptake in 2021?

Murray, let me take one quick shot. So on Alström's, there is a clear signal in Alström's. What we have to decide is do we have a fileable data package. The total number of Alström's patients treated today between the 6 and our Phase II and -- sorry, the 4 in our Phase II and the 6 that were treated in the data released in December, it's a total of 10. So in that group, we have 1 clear -- I think probably 2 clear patients at 20% response rate. I know anecdotally, outside of data reported, there's at least 1 more. So my point is that we know there's a signal there, as with many of these genes, not every patient may respond. So we may be back in a world that says those Alström patients have a right to at least getting their 12-week trial and the drug to see if in fact, they'd fallen a responder group. That might be one approach. The -- as to when we will make a decision, it will be when we have a chance to see the full data set coming out at the end of the first quarter with all of the additional ancillary endpoints, and we can make a decision then as to whether we'll file with Alström or not. But we're not going to give up on Alström. There's not 0 signal there. I think -- Murray, anything else you want to add to that, sorry?

Yes. Just the small data's come on Alström's. A lot of those physicians talk about the metabolic effects. So you've got to not just look at the weight. So we know there was a reduction in hunger. We need to look at quality of life when we completed the data set as well as metabolic changes. So you may get some change in tax distribution, metabolic changes because Alström is more a metabolic condition with diabetes than say, BBS. So as David says, we need to do more before we say no.

And I think, Dave, the last question was just on IMCIVREE. So we do not yet have our first commercial patient. We're just getting our commercial drug ready to put into the field. So that will be happening imminently. And so that will happen over the first quarter. The number of patients that you should expect, again, I'm sorry to be a broken record, it will be in the 10s over the first 1 to 2 years. It's not a number that I'm angsting over. What I'm angsting over is making sure that we can execute on that list of activities. So I might put up there at the end between the BBS filings and getting these trials going, and the efforts to support enrollment into those 2 trials. It's going to lift all boats, including the approved indication populations for IMCIVREE.

Great. Thank you. And our last question comes from Arlinda Lee at Canaccord. Can you talk about the weekly formulation? What kind of trial you are planning? And have you spoken with the FDA about this? And when can we expect that data?

Okay. So last year, we presented the weekly formulation in general obese. The next stage is to do the weekly formulation in the risk population. We're probably doing the weekly in Bardet-Biedl. And we'll do probably 2 weekly studies. One will be a switch, so we've got to take who are on daily. And people who -- Bardet-Biedl who are doing well or people in the long-term extension with POMC and show they can switch from daily to weekly. So that would be a 3 to 6-month switch study. And then we want to say, well, actually, our people find starting to know. So with BBS, which is a younger population you're seeing weekly would make sense. So we probably do a de novo study in BBS and a switch back. So they're the 2 studies. We've actually done something very unique, not totally unique, but something that I think is a bit forward. We've actually set a briefing document to the U.S. and the European, and we're on a joint time line with them. So Europeans in the U.S. will be giving us input into those designs and those plans in parallel. And that's happening in the first half of this year.

Thank you, Murray and David, I'll turn it over to you for just a brief close.

Yes. Good. Thank you to all who participated here and all of you who are listening in. Maybe just one additional comment before the final thank you. We've been -- this today's presentation, which was a condensed R&D Day, for sure, was heavily U.S.-centric. And I just want to remind people, the numbers, the epidemiology, the 100,000 to 200,000 calculation is a U.S.-only number. And Rhythm is global. We are not adopting a strategy of a small U.S. biotech that says, we'll focus on the U.S. and ignore the global or kind of get to it time. We're actively pursuing a global strategy. Our clinical development plans are global. Our KOL network is global. We have an emerging international organization based out of Europe, but it is international in scope early efforts in Latin America, and obviously, are looking to understand Asian opportunities as well and very focused on the European opportunity. So these will go in parallel. Always have believed that health care problems know no geographic boundaries. And we have a unique solution for a true unmet medical need and we'll do the best to get it patients globally. So that's where we are. I'm really excited about Rhythm's progress to date. I think it's just been an amazing year, but built in a very solid, careful, thoughtful, step-by-step way. And as I hope you've heard and understood, giving us a lot of confidence in what's to come on both how we pick the genes and the strategy for developing those indications. So thanks again. We look forward to providing further updates as we go forward. Good day.