Day, thank you for standing by. Welcome to the Rhythm Pharmaceuticals Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Dave Connolly, investor relations. Please go ahead. Thank you, Daniel, and good afternoon, everyone, and welcome. This afternoon we issued a press release with the phase III top-line results for our EMANATE trial. You can access the press release as well as the slides that we will be reviewing today by going to the Investors section of our website. Listed on slide three are the speakers for today's call. David Meeker, Chair, President, and Chief Executive Officer, will walk through these data. Dr. Alastair Garfield, our Chief Scientific Officer, and Hunter Smith, our CFO, are available to answer questions on this call as well. Before we get started, I would like to remind everyone that these statements we make on this conference call will include forward-looking statements. Actual events or results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in the risk factors in our risk factors section of our SEC filings. In addition, any forward-looking statement made on this call represents our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements. With that, I'll turn the call over to David. Thank you, Dave. Thank you all for joining this afternoon. It's been a long road, ending not exactly where we had hoped, missing the primary endpoint in all four cohorts, but with some positive elements which will position us well going forward. As expected, we saw positive signals in the POMC HET cohort. Somewhat unexpectedly, the SH2B1 cohort was negative. Surprisingly, we did see a clear signal in the SRC1 cohort. We will look at each of these in greater detail. We continue to look forward to our March 20 PDUFA date, and I will now have no further comments about that on today's call. In addition to the signals in the POMC and SRC1 cohorts, we have learned more about each of these genes, which will position us to design a better study going forward. We know patients with impaired signaling through the pathway have a difficult time losing weight with diet and exercise, and we have not seen a clear placebo effect in any of our trials. The stronger placebo response in some of the cohorts is consistent with a larger number of patients having benign variants and a pathophysiology more consistent with general obesity. Finally, this trial suffered from an exceptionally high dropout rate, which becomes extremely challenging when you perform the conservative multiple imputation analysis on the primary endpoint. Slide six shows the top-line data. The values are the least squares mean difference between setmelanotide and placebo for the modified intent-to-treat analysis using multiple imputation for the missing data points. As you can see from the P-values, we missed the primary endpoint analysis for each of the four genes. Now, before we dig more deeply into the data, let's briefly revisit how we got here, beginning on slide seven with a familiar cartoon of the MC4R pathway. Our approach to identifying genetic populations likely to respond to setmelanotide was always a heuristic process based on evolving scientific and clinical data that supported MC4R pathway dysfunction as a contributor to obesity in these patients. The genes under investigation in our EMANATE study all impact POMC neuron function and are predicted to reduce alpha-MSH, suggesting that replacement with setmelanotide would be effective in reestablishing pathway function and reducing body weight. The success of this approach is predicated on understanding that the gene variants we enrolled do indeed compromise MC4R pathway function. As shown on slide eight, this variant classification process is a significant challenge for both the medical genetics field and Rhythm, in no small part due to the fact that scientific understanding of variants is always evolving, leading to a dynamic classification process. For our POMC, PCSK1 and LEPR HETerozygous cohorts, we had a good understanding of our enrolled variants that enabled more accurate patient enrollment, which, as you will see, is borne out in our genetically confirmed cohort analyses. By comparison, much less was known about the SRC1 and SH2B1 cohorts, where almost all variants are classified as VUS, variants of unknown significance. As a reminder, on average, only 20% of VUS variants end up being classified as pathogenic or likely pathogenic. The gray box in the upper right corner shows which variant classifications were enrolled in each cohort. For POMC, PCSK1, and LEPR HETs, we enrolled pathogenic, likely pathogenic, and suspected pathogenic variants. The latter representing variants still classified as VUS, but the data is increasingly pointing towards that variant being pathogenic. For SRC1, all patients were VUS, whereas the SH2B1 gene had a mix with the 16p11.2 deletion patients, by definition, having loss of function of the gene. Slide nine shows the number of patients enrolled in each cohort, which is noteworthy for the small number of patients in the leptin receptor het cohort. This is an extremely rare indication, and we were not able to enroll fully. The trial design was a standard double-blind, placebo-controlled trial randomized one-to-one with a primary endpoint of change in BMI at 52 weeks. Slide 10 shows the demographics which were similar across cohorts. On average, patients in each group suffered with severe obesity with BMI values greater than 40. The adverse event profile, as shown on slide 11, is similar to other trials run with setmelanotide, with injection site reactions, GI complaints, and hyperpigmentation being most common. Slide 12 shows the dropout rate with on average 40%-60% of patients discontinuing. With the exception of the LEPR HET group, with a very small number of patients, the dropout rate was similar between treated and placebo patients. Slide 13 shows the reasons for discontinuation, aggregating patients across all four studies. Patient decision was the most common reason for patients on placebo, and adverse events were the most common reason for patients on setmelanotide. Now, beginning with the POMC HET cohort on slide 15, let's dig into the clinical data. As you might expect, we have looked at the data several ways. We missed on the primary endpoint in the modified intent-to-treat population using the conservative multiple imputation method required by regulatory authorities, where the imputed data is informed by the opposite arm. Specifically, a patient who discontinues in the setmelanotide arm, at whatever time point, will be considered as though their outcome at week 52 was the same as the placebo group. On slide 15, we show a post-hoc analysis using the last observation carried forward methodology, where the last value a patient has prior to discontinuing is used for the final analysis. This showed a highly statistically significant difference of 5.53% for the same modified intent-to-treat population. Moving to slide 16. As noted in the intro, we had utilized an in vitro assay to assess loss of function for each of the variants in the POMC and LEPR genes. This allowed us to classify variants pathogenic, likely pathogenic, and suspected pathogenic. The study protocol included reconfirming the genetic eligibility and variant classification for each patient in order to conduct a pre-specified analysis for genetically confirmed patients. That reconfirmation resulted in a net 11 patients being removed for not having that genetic confirmation. On slide 16, we show, using the last observation carried forward methodology in the genetically confirmed cohort, a statistically significant difference of 6.8%. Slide 17. Finally, using the rationale that a response to setmelanotide, a highly specific peptide for the MC4R receptor, provides further evidence that the MC4R pathway is central to that patient's disease, we looked at those genetically confirmed patients who completed the study. This additional post-hoc analysis showed a highly statistically significant least square mean difference of 9.7%. The short story for the LEPR HET cohort is summarized on slide 19. These patients were hard, rare and hard to recruit. A small number of patients recruited had one variant which on reanalysis was down-classified by our central lab. We do not anticipate doing further work on this patient population. The SRC1 cohort, as we have highlighted multiple times, by virtue of the fact that all variants enrolled were classified as loose, had a low probability of success. Despite that, the primary endpoint modified intent-to-treat analysis with multiple imputation for the almost 60% of patients who discontinued from this cohort, was a least square mean value of -4% and showed the strongest trend towards significance with a P- value of equal to 0.12. On slide 21, in the same post-hoc analysis we performed for the POMC HET patients using the last observation carried forward methodology, we saw a highly statistically significant least square mean difference of 6.24%. On slide 22, we looked at the post-hoc analysis of genetically confirmed patients who completed this study, where we saw a statistically significant difference of 8%. Finally, on slide 23, to give you an example of the process by which we can work to better understand loss of function and the ability of patients with a true loss of function variant to respond to treatment, we examined those patients who had a variant in the critical binding domain for the protein, for the SRC1 protein. 19 patients carry this variant, with 12 of the 19 completing the trial. In those 12 patients, the placebo-adjusted difference was 12.7%. The most disappointing cohort was SH2B1 16p11.2. We had hypothesized that the 16p11.2 deletion patients, who by definition would have loss of function of the SH2B1 gene which is embedded in the deleted region, should respond. The modified intent-to-treat showed no effect on average, and when we looked at the genetically confirmed completer analysis shown on slide 25, the difference was only 3% and not statistically significant. A further analysis looking only at the known loss of function 16p11.2 patients on slide 26 similarly showed only a modest effect which did not reach statistical significance. In summary, we are disappointed by the top line results, but encouraged by the findings in the POMC HET and SRC1 cohorts. We will continue to interrogate these and other Daybreak genes from our phase II study to improve our ability to determine loss of function variants. Our priorities going forward for our next generation therapies will be the HO studies, the Prader-Willi studies, BBS studies, and patients with confirmed loss of function genetic variants. Patients with genetically impaired signaling through the MC4R pathway represent a significant unmet medical need, and addressing that need is one of the three key pillars of Rhythm's strategy. The other two, as you know, are anatomic abnormalities of the hypothalamus, of which acquired HO is perhaps best known, and we look forward to the upcoming PDUFA date. The third pillar is Prader-Willi syndrome, a genetic disease but with unique challenges and representing a large unmet need. I wanna close by thanking the patients, their families, and our clinical investigators and their teams. This trial was not easy. It was statistically negative but not negative in terms of the learnings, which will move us closer to developing a meaningful treatment for these diseases. With that, we can open it up for questions. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. In the interest of time, we ask that you please limit yourself to one question. Please stand by while we compile a Q&A roster. Our first question comes from Phil Nadeau with TD Cowen. Your line is open. Good afternoon. Thanks for taking our question. Just a question on next steps to dive in a little bit further. It seems like the imputation analyses that you did, computing the placebo would have done are very conservative and maybe not appropriate for a study with such a high dropout rate. I guess first part of the question is, why was that the imputation method that was chosen? Then second, on next steps, it sounds like you're not gonna take the data to the FDA to see if like the completer analysis or LOCF could support a filing. Is that fair? Yeah. Taking the second part of the question. That's correct. We're not gonna file on any of these. So I think the way we're looking at this data, if it was vastly positive, we would, of course, as we've said, taken that to the regulators, FDA. Your question about whether they would accept a different approach, no. I think they're across all of our programs, they've used the same, call it conservative, they would call it standard multiple imputation analysis. We used it for HO. If we'd done a last observation carried forward, even in that trial with a much smaller dropout rate, we would've had a slightly better result, which was, you know. It is a more favorable way of looking at that. The value in doing it that way is to help us internally. I think our goal was to try to use this data to understand does it work in that gene or not? I think we're exiting this saying, I still think it works on leptin receptor HETs, to be honest. That's so rare. That was challenging to recruit. I think it's unlikely, as I indicated in my comments, that we would do more work. SH2B1, that was pretty negative. It's not 100% negative, but you know, I think, you know, we're not gonna rush there to do additional work. Whereas for the POMC HETs and the SRC1, I think we will. It won't be the highest priority coming out of you know, the list of things that I put forward there. We will get to that. Does that answer your question, Phil? Yeah. That's very helpful. Thanks for taking our question. Thank you. Our next question comes from Tazeen Ahmad with Bank of America. Your line is open. Okay, great. Thanks for taking my question. I just wanted to ask about the potential of looking at these same basket indications for your next gen assets. Based on what you saw for setmelanotide, does that, you know, reduce your interest in looking at the ones that didn't work for the follow on compounds? If not, can you give us a sense of how you're thinking about when you might try to look at the next gen compounds in these indications? Thanks. Yeah. Thanks, you know, Tazeen for allowing me to clarify that. Yeah, all additional work, future work will be done with the next gen. We would not go back and run another trial with setmelanotide in these. I think this data is relevant in the regulatory conversation, and we know that, and that it's providing with these subsequent, some post-hoc, some not post-hoc. These subsequent analysis, I think, give us reasonable confidence. I think regulators would look at this as supportive evidence for the role of MC4R in these indications. Then we'd need to run a positive trial with one of the next gens, which we would do. As I mentioned in my response to Phil, our initial priorities, not surprisingly, are going to be to run the HO studies. Definitely getting Prader-Willi up and running as quickly as we can. We wanna have the next gen run in DBS so that we check the boxes on our approved indications and get those taken care of. You know, we'll be looking at the additional genes, and we'll be weighing both what we've learned here and also what we know from what we learned in our daybreak studies. We'll, you know, begin to pick. There's, you know, probably five plus or minus genes across this group, which would be of the highest priority. Next question. Thank you. Our next question comes from Derek Archila with Wells Fargo. Your line is open. Hi, good evening, and thanks for taking the questions. Just wondering if the level of discontinuations you saw in the trial were expected. Maybe just remind us how these populations are different from Bardet-Biedl and HO in terms of sensitivity to adverse events seen with setmelanotide. Thanks. Yeah, it's a good question. I think there's more for us to learn here about exact reasons why, but you know, just to highlight a few things. Let's take Bardet-Biedl, where we had a 20%+ discontinuation rate. You know, those patients, many of them, had caregivers who were working with them, so there were other support structures around them, which made it easier for them to stay in a trial. We also had a shorter placebo period. HO, in contrast, was a full, you know, year study. Most probably also had supportive structures around them to a higher degree than this population, but they also were seeing a larger benefit. You know, motivation to stay on there might have been greater. I think you know, this trial we started running back in 2022. It's been going for a long time. We are running against the emergence of GLP-1s, for example. I think, you know, there's a lot of patients in this study who, you know, might have been looking over the fence at other things, some they could be taking if they weren't seeing a dramatic response, some. You know, being in a trial like this has a pretty significant burden in terms of commitments, the number of tests that need to be done. There's no one answer but, you know, the aggregation of things, timing, level of burden, you know, not the most dramatic response, on average, I think left us where we are with a high discount rate. Understood. Thank you. Okay. Thank you. Our next question comes from Seamus Fernandez with Guggenheim Securities. Your line is open. Hi, this is Evan Lang on for Seamus. Thanks for the question. Just following up on some of the discontinuation rates. Any more details you can provide on specific AEs or subject decisions that comprise a more majority of dropouts versus some of the expectations? Really just curious sometimes what to mitigate with the next gen bivamelagon or RM-718 assets. I'm wondering if this is more setmelanotide related or, you know, whether, you know, there's other optimizations that can be done. Second, just curious in terms of prioritization of next gen assets here, which ones you may think could be more appropriate? Then, third, is there an opportunity to further exploit dose for patients reaching max dose with setmelanotide? Thanks. Okay. You're breaking the one question rule there. I will. Let's see what we can do here. I think in terms of discontinuations. The split, as we said, the placebo group was basically patient choice, and that's everything, you know, mostly the list that I ran through. I think those in the setmelanotide group had adverse events. The adverse event profile, again, is highlighted exactly what we've seen in the other trials where we didn't have that kind of discontinuation rate. I think you couple an adverse event with maybe, you know, not getting the result that they had expected, whatever. You know, that is invariably a combination of factors for them. How do you run a better trial? I think, you know, the focus on running a better trial will be taking what we've learned from this, and we have learned, there's stuff we're in the process of learning today, to be honest with you, about how to better identify patients with true loss of function. You take that into the next trial, which says, you know, we wanna minimize the number of patients who don't have true loss of function. They're not gonna benefit. If you can, you know, truly be more specific about the true loss of function, you know, again, to run a better trial. Then it's just execution on the trial. You know, there are things that we just didn't execute on well, either as a company or as a CRO we're working with. You know, those are learnings. Again, Rhythm, we've matured a bit as a company. I think we can just run a better trial. The bigger factor will be getting you know the right patients in, of course. Your question about higher doses, I don't think. You know, that's an interesting question. You know, when we come to the next gens, I mean, they're not apples to apples in terms of dosing. So, you know, what is the dose for the weekly and what is the dose for the daily oral? We'll figure that out. I think for any population we're in, we're always asking the question of you know are we in the right dosing range? You know, for set, I think somewhat luckily for the most part, we have been. We'll continue to ask that question going forward. All right. Thank you. Thank you. Our next question comes from Corinne Johnson with Goldman Sachs. Your line is open. Thanks, and good afternoon. Maybe you could talk a little bit to your last point about the trade-offs between getting more specific on identifying the patients that would respond best to the therapy versus, you know, the pace of enrollment and finding those patients. Related to that, how has the genetic testing progressed, if at all, since you started MNA, that you could kind of take advantage of in a future iteration of this program? I'm gonna take the trade-offs part of it. You know, as you know, Corinne, my background in rare diseases have really been shaped by. I think this is true across all medicine, certainly works, or all diseases, certainly works in rare diseases. You wanna get responders. You know, the more diluted you are by, you know, patients who don't respond, even though you can feel good about a quote-unquote higher, faster rate of enrollment, you're not serving anybody. You know, you end up in a place where we are today, probably with a non-significant result. We probably could have done better if we'd been able to better identify the patient. That's gonna be the highest priority. I think we have insights into that, certainly for the POMC HETs and for the SRC1 that will allow us to, you know, be better at that. The genetic testing is a key part of the genetic strategy, and I think, you know, many of you have heard us talk about this, which is, you know, Rhythm's goal is not to be a testing company, but we recognize in the rare disease space, you know, the company often has to provide the testing. We do that today. We've learned a lot from that. Our goal ultimately, as we get more genetically driven diseases approved, then the value of testing goes up. You're running a panel, and if you're looking for one, your hit rate off the panel will be low. If you have five potential genes on that panel, which might translate to responding to therapy, then by definition you'll have a higher hit rate and you're likely to test more. There's a virtuous circle that we'll be entering into as we begin to develop this further. Ultimately, you know, back to us not being a testing company. As obesity evolves here, you know, Well, multiple things will happen, but one of the things that's gonna happen is as GLP-1 use, you know, becomes broader, it's, you know, not everything. You know, it's a hammer and everything's a nail, that's no longer true. Increasingly people will recognize GLP-1 failures. How do they work them up? One of the obvious things you can do is test those patients for their genetics. These things are gonna come together and you know, Rhythm and the MC4R pathway diseases are gonna surface, I think, in that kind of dynamic. I don't know. Did I answer your question? Yeah. Thanks. Yeah. Okay. Thank you. Our next question comes from Mike Bowles with Morgan Stanley. Your line is open. Hi, this is Rohan for Mike. Thanks for taking our questions. Due to the rare nature of these genes, is there anything that you can do to accelerate enrollment for future next gen trials? How much did hyperpigmentation contribute to discontinuations? Thank you. Yeah. On the second part, I don't know. I mean, that's probably in the data set. I don't know it today. I'll just answer that by saying, overall of our experience, hyperpigmentation is about 5%. Of patients who discontinue, about 5% of it's due to the hyperpigmentation. I would guess it's probably similar here, in terms of overall percentage. What can we do to accelerate enrollment? That's just increasing testing and increasing awareness. I, like I said, really think this dynamic of patients who fail to respond to GLP-1s, that world is, you know, exponentially growing. The pool of patients who have a history of early onset obesity who fail to respond to a GLP-1, they're gonna be prime candidates to be tested. One of the things about the VUS challenges that, you know, we talked about, which is, okay, you got tested, but your results show that you have a VUS, I don't know what to do with that. If you are an individual who's failed a GLP-1, had a history of early onset obesity, and certainly if you had hyperphagia, the probability that your VUS is pathogenic is higher than if you're just a random individual with a variant in that gene. I think these are things that will increasingly make the next trial easier to run and to recruit into. Thank you. Thank you. Our next question comes from Jon Wolleben with Citizens. Your line is open. Hey, t hanks for taking the question. Just wondering if you'd talk a little bit more when you say additional work with the next gens, what that could look like. Would they be smaller phase II studies or a chance for, you know, a phase II, III pivotal program? Yes. Here's one scenario. The first thing I want you to take away is the priorities for Rhythm right now are, you know, these more important from a company strategic standpoint, trials, the HO, RM-718 world, and BBS as indicated. On the genetic side of the equation, there's some investigator initiated work going on now. You could imagine, and we're looking at it, that some of the syndromes where by definition if you have a syndrome, we know you have loss of function to the extent that we have some insight into that through early proof of concept, then we might run a study there and we would run one study. Call it a two-three, whatever. I think... The dosing for the most part, when we say two-three, you sort of, you know, the two part is trying to figure out your dosing and the like. We'd run one trial and, you know, however we would have to design it. We, you know, for each of these, genetic, it would be only one trial. To the extent we go back to POMC HETs, for example, or SRC1, this data, as I said earlier, would be supportive in that regulatory filing in terms of, you know, the role of MC4R pathway, and we would be enrolling patients with a slightly narrower scope, but with a higher probability of, having, you know, loss of function in their gene. Got it. Thank you. Thank you. Thank you. Our next question comes from Lisa Walter with RBC. Your line is open. Thanks so much for taking our question. Sounds like the plan is to explore development path forward with the next gen MC4R agonist, but I'm wondering what the strategy might be to ensure fewer placebo arm discontinuations going forward, even with these next gen assets. Any color here would be helpful. Thanks. Yeah. I mean, that's a challenge. I think so, aside from just supporting patients in any trial, which is what, you know, a well-run trial does, you just try to get patients to hang in there. I think we did a really good job in our HO study and those patients hung in there. One of the things that helps placebo patients stay in is A, a belief that they don't have other good options. I'm a GLP-1 failure, nothing else has worked, this is my hope, and I know that when I finish the trial, then I have a shot at I will get the drug. That's the biggest thing. Secondly, back to expectations of, you know, having a reasonable response. You manage placebo by groups, by having the reward at the end, be meaningful to them. In addition to the just general support. Next question. Thank you. I'm showing no further questions at this time. This concludes the question and answer session. I would now like to turn it back to David Meeker for closing remarks. Okay. Well, thanks everybody for tuning in on short notice here. Back to where I started. I'm disappointed in this, but actually this is a solid building block going forward. I think you've heard me speak before and you'll hear me speak again, I think. I'm pretty excited about where Rhythm is and all the things we have coming down the pike here. We look forward to our next conversation. Thanks. This concludes today's conference call. Thank you for participating. You may now disconnect.