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

Ladies and gentlemen, thank you for standing by. Welcome to Rhythm Pharmaceuticals Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would like now to turn the conference over to Dave Connolly, Head of Investor Relations. Please go ahead.

Thank you, Michelle. Good morning, everyone, and welcome. This morning, we issued a press release announcing that the preliminary data from our exploratory Phase II trial showed setmelanotide demonstrated a positive efficacy signal in Prader-Willi syndrome. 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. David Meeker, Chair, President and Chief Executive Officer of Rhythm Pharmaceuticals, will present these data this morning. We are also joined on the call by Dr. Jennifer Miller, University of Florida -- a Professor of Endocrinology, excuse me, at the University of Florida in the Department of Pediatrics. She is the principal investigator for this Phase II trial. And Hunter Smith, our CFO, is also here and available to answer questions on this call as well. Before we get started, I'd like to remind everyone that the 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 section of our SEC filings. In addition, any forward-looking statements made on this call represent our views as of only 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, who will begin on Slide 5.

Thank you, Dave. Good morning, everybody. Thank you for joining the call. Today, we're sharing preliminary data from our open-label Phase II study in patients with PWS as the data have reached the point where we can make some important decisions about the next steps in the program. We are running the trial as a single-center study at the University of Florida with Dr. Jennifer Miller, who joins us on the call. We are pleased to announce positive changes in BMI and HQ-CT at 3 and 6 months and short of new information, which is inconsistent with what we have seen to date, we will proceed to a Phase III program in PWS. More on that later. Furthermore, based on these promising early data, we have initiated a Part D arm in the Phase I study of our weekly MC4R agonist RM-718, where we will test 718 in up to 20 PWS patients. That amendment has been filed, and we anticipate screening our first patient this month. We have received many questions leading up to today as to how we will interpret the study and what is the bar we need to hit to proceed to a Phase III study. We have been clear, we would analyze the data patient by patient, trying to understand the context around each patient and their response to treatment. And that the bar would be results, which gave us confidence we can run a successful Phase III study, achieving a 5% reduction in BMI at 1 year. We have completed enrollment with 18 patients treated to date. Today, we are sharing the data from the first 8 patients who reached 3 months or more and the 5 patients who reached 6 months or more. We entered this study with conviction that the MC4R pathway plays a critical role in the underlying biology and a very realistic view of the challenges of running clinical trials in patients with PWS. A major advantage of working with Dr. Miller, who is one of the world's leading experts in PWS is a deep understanding of the patients she follows. She has a large practice, and she knows not only the patient, but the family, which is invaluable and trying to interpret some of the individual patient responses. She will share some of her thoughts once I have reviewed the data. I want to start with a short introduction to PWS beginning on Slide 6. PWS is a severe complex multisystem disease characterized by hyperphagia, a severe preoccupation with food, often accompanied by abnormal food-seeking behaviors and reduced energy expenditure, leading to severe obesity in the majority of patients unless their energy intake is rigorously restricted. There is a significant unmet medical need with limited therapeutic options to manage the hyperphagia, decreased energy expenditure and consequent weight gain. U.S. prevalence is estimated at approximately 20,000 patients with a similar frequency of the disease in other parts of the world. Moving to Slide 7. This cartoon attempts to capture the complex pathophysiology underlying this disease. Multiple genes are involved, including at least 2 genes which can directly impact signaling through the MC4R pathway. We have talked specifically about MAGEL2 loss of function variants, which are present in virtually all patients with PWS, we studied in our Phase 2 DAYBREAK study. The response in those patients gave us optimism. We would see a response in PWS. While multiple factors may contribute to the hunger in abnormal behaviors in PWS, we believe a central part of the pathophysiology affecting satiety and energy expenditure is a deficiency in the MC4R pathway and therefore, our interest in studying setmelanotide. Before getting to the data, we also want to provide some historical context. Most PWS studies have failed and no therapy is approved for weight or BMI reduction. On Slide 8 is beloranib data from 2016, which is arguably the only drug that has shown meaningful changes in weight in PWS patients. That trial was stopped early due to thrombotic events and development of the drug was discontinued. However, it is a useful benchmark. They observed placebo-adjusted decreases in weight at 6 months of 8% and 9%. Importantly, however, the actual weight decreases in the trial were 4% and 5% at the 2 doses with the placebo group gaining weight, supporting the view that simply stopping weight gain in PWS is clinically meaningful. Slide 9 shows the results for a cohort of patients from our original trial of setmelanotide and PWS conducted in 2016. Of the 4 patients who received the highest dose of 2.5 milligrams for 8 consecutive weeks, 3 of them lost weight, thereby suggesting setmelanotide could have a meaningful clinical effect. Slide 10 shows the very simple open-label trial design. 18 patients aged 6 or greater were enrolled. Each patients dose escalated to 5 milligrams daily as tolerated for patients less than 12 years of age or dose escalated to 3 milligrams as the maximum dose. Endpoints in addition to safety and tolerability included change in BMI, HQ-CT scores and body composition. Slide 11 shows the demographic data for all 18 patients enrolled to date. We have a very good mix of patients by age with 3 of them younger than 12 years old, 4 between the ages of 12 and 18 and 11 patients 18 or older. They all suffer with severe obesity with a BMI for all 18 patients. Today, we are focused on the 8 patients who reached month 3 and setmelanotide and their baseline BMI was 43.7 on average. 5 patients reached the 6-month mark and 1 patient discontinued prior to their 6-month visit. Of the 18 enrolled patients, 17 patients remain on active therapy. Now let's move to the results. On Slide 12, there's a bar graph showing the percent BMI decrease at 3 months for the 8 patients. Underneath each patient number is the patient age, sex and starting BMI. Four patients denoted by the asterisks had diabetes and in 2 patients 1 and 3, it was poorly controlled. The V denotes the 2 patients who are on Vykat, patient 6 and 7. 6 of 8 patients had a decrease in BMI ranging from minus 1.3% to 4.8%. We will discuss in more detail the last 3 patients, 2 of whom had gained weight at 3 months and patient 5 who subsequently began to gain weight during a period of what we believe was noncompliance. Slide 13 shows the HQ-CT results. Think it is recognized that this is not the best tool to capture clinically meaningful changes in patients with PWS, but it is validated and it has served as the basis for a recent approval. This trial was not designed to capture changes in HQ-CT and that it is an open-label study, and there is no requirement for a baseline level of severity. For example, one patient, as you can see, had a 0 score at baseline and their score has remained 0. Since it is an open-label trial, the results cannot be compared with data from other blinded trials. However, it is additional data, and it gives us confidence that patients are experiencing meaningful changes. 6 out of 7 patients with an elevated score at baseline showed a decrease in score. Patients 6 and 7 are both on Vykat which might explain their lower score on entry and both moved modestly further down with setmelanotide treatment. Moving to the 6-month data on Slide 14. Shown here are all 8 patient data at 3 months in dark blue and then the 6-month data in light blue for the 5 patients reaching the 6-month mark. Patients #3 and #2 have cleared the 5% level. Patient 6 is flat from 3 to 6 months at approximately 2.5%. But his DEXA scan tells an interesting story, and I'll show you that on the next slide. On Slide 15, we have the DEXA scans from 4 patients at 6 months. Patient #1 was too heavy for the DEXA machine, so we have no scan. The first 3 patients all show more fat than lean loss with fat mass decreasing by approximately 8% in the first 2 patients and more than 10% in patient #6. Patient #6 is the patient whose BMI had plateaued at approximately 2.5% at month 6. The DEXA scan results would suggest he was having a much more meaningful response to therapy than suggested by the BMI. Patient 5 gained fat mass consistent with the increase in his BMI. Now let's go back to the summary data at 3 and 6 months repeated on Slide 16 and provide a little more color around the 3 patients who did not decrease their BMI at 6 months. Patient #4 was only intermittently compliant initially and then discontinued the trial prior to reaching the 6-month visit. Patient 5 had a good initial response, actually losing 4% in BMI at 2 months, but then traveled out of the country over the summer with what we believe to be poor compliance with treatment. He is now back home on treatment in a more stable situation and decreasing his BMI again after his 6-month visit. Finally, patient #1 is the most complicated patient. Dr. Miller can provide more background, but she entered the trial with a BMI of 67, gaining weight steadily prior to trial entry, very poorly controlled diabetes and gained further weight with some improvement in her diabetes management. She also has severe lymphedema in her lower extremities with the edema likely complicating some of the weight measurements. Her BMI has been relatively stable since our initial trial weight gain. And of note, she did have a decrease in her HQ-CT score from 20 to 11. Slide 17 lists the AEs for all 18 patients. Setmelanotide has been very well tolerated in this population with the majority of patients getting to 4 or 5 milligrams. The AE profile has been similar to what we've seen in other populations with hyperpigmentation and injection site reactions being most common. So with that, I'd like to turn to Dr. Miller to get her thoughts on the program. So Dr. Miller, thank you for joining this morning on what I know is an incredibly busy clinic day, and I also know you're actually calling from clinic. So the first -- the first question, just what type of patients did you enroll initially and why? So maybe you could give us a little background there.

Sure. So the first 5 patients I enrolled were patients that were basically what I described as the worst of the worst. I mean they were people that would not have qualified for Vykat therapy because of their medical conditions. They were all morbidly obese. They -- many of them had type 2 diabetes already. Many of them had lymphedema, which was going to make it difficult to determine if they develop worsening edema from Vykat, I felt that I would be unsure as to whether or not that I could assess that adequately. They also all 5 had untreated obstructive sleep apnea. And so again, I was worried about putting them on Vykat with the risk of edema that comes with that. And so basically, they were patients that were at the end of the road in my personal opinion. And I said to these families, like we have no other choice, like we can't do Vykat. There's really nothing else out there. We're doing this trial. Let's try it. It's worth a try. There's really nothing else. Patients 6 and 7 who you showed data for who are on Vykat had done well with Vykat , as you saw from the hyperphagia scores in terms of improvement in hyperphagia severity. However, both were large individuals to start with prior to starting the trial, both did develop type 2 diabetes on Vykat on DCCR during the trial and were -- the diabetes was somewhat difficult to control. So I had asked to put them on to this trial so that we could see if setmelanotide did indeed cause weight loss, maybe we could get their diabetes under better control just with some weight loss or as we saw in patient #6, maybe some redistribution of body composition with less fat mass and more lean muscle mass. So again, and I say this a lot, these patients were at the end of the road, unfortunately, and they are at the end of the road if -- this is kind of it. And so they all know that and their families know that, but I'm very grateful to them to trusting me to do this trial and see if it works.

Perfect. So maybe -- I mean, you've been involved with many trials in Prader-Willi patients, if not all of the trials. So how would you interpret these results? Can you give us a little context for how you see the changes we're seeing today?

Well, I've been very excited about the changes that we're seeing in BMI reduction and body composition in the great majority of the patients. Their diabetes control has improved with minimal to no adjustments in their diabetes regimen other than patient #1. They just -- they're moving better, their body composition looks better. There -- the parents feel that they are eating somewhat less, that they're less obsessed by food and that they're able to exercise more easily and that they're choosing to exercise on a regular basis, which is remarkable to me.

So and, maybe you were also a lead investigator. I think you enrolled close to 20 -- approximately 20 patients in our HO040 study. I'm just curious in terms of biologic effect of an MC4R agonist like setmelanotide, are there any similarities? The diseases are quite different, but any similarities in terms of what you're seeing?

Yes. Yes, definitely. I mean, yes, the diseases are quite different. It was -- I was hoping for the same degree of magnitude of results that we saw in the HO trial in this population. But as you point out, it's a completely different disease. But the similarities that we saw in both groups are what I mentioned before, the increased tendency to want to go out and do stuff and exercise increased happiness, like everybody reports that less irritability. That was something that was consistently reported in both groups across the board after about 2 months on setmelanotide, that was a consistent finding. So those things were all very, very positive to me.

And going back to the challenging patients. So patient 5 and patient #1 have gained weight since they started the trial. So why would they stay on therapy?

Because -- yes, good question. They really feel better on the drug. Both of them, when I've threatened because I've been worried about noncompliance and I've said, probably we should stop if we can't be compliant. And both have had major furniture type throwing meltdowns here about having to come off of the study because they both feel that they are doing better on the drug. They feel happier, they feel better overall. They themselves. This is not a parent perspective. This is the people perspective. And so they really don't want to stop the drug. They perceive that it's helping them significantly.

So I know we didn't collect formally their prior weight loss history as part of their case report forms and the clinical trial specifically, but you followed a number of these patients for a long period of time. Were they gaining weight and specifically patient 1 and 5? And what was their natural history coming into the trial?

To be clear, I followed every single one of these patients in this trial since they were infants. So for a very, very, very long time. And so yes, every one of them was gaining weight excessively prior to entry into the trial. And the ones who are not on Vykat, so the ones who are just on setmelanotide at the entry to trial are we're gaining weight at a pretty rapid clip at every clinic visit that I saw them at, no matter what we tried to do to intervene, we were unable to slow down their weight gain. And this has slowed it. I've said to the parents like stable to me is a win. When your kid was gaining, gaining, gaining and the BMI was 110% of the 95th percentile, and now it's just kind of hanging there. So crossing percentiles as these are -- some of them are teenagers, right? So they're growing and their BMI is actually improving because they're growing. And the adults are at least hanging stable and not continuing to go up. I consider that a very big win from a metabolic health perspective.

Perfect. So maybe last thing, anything else that strikes you? Again, we're early in the trial, and we're going to let the data mature, of course, but welcome any additional thoughts you have.

No. I think overall, with the exception of a couple of patients, compliance has been really good, considering it is a daily injection. But these are patients that are used to taking daily injections. Most of them are on growth hormone. And as you mentioned, many of them have type 2 diabetes and are on insulin for that. So no, I think it's been exciting to see, and it's been exciting for the families to see the changes in their children's body composition.

Okay. Great. So thank you. So I have a couple more comments to make, and then we'll open it up for general Q&A. But thank you, again, for your efforts those of your PWS patients who volunteer for the trial, these early trials, of course, any of these trials in PWS are not easy. So now for a few concluding remarks before opening up the Q&A. We recognize these results are early and preliminary. However, as you know, in these rare disease populations and particularly with small data sets, we put tremendous emphasis on the results from each individual patient, those who are responding to the treatment and even more attention to those who may not be responders. Are they true nonresponders? Or are there mitigating factors? So for the first 8 patients, the BMI is 6 of 8 patients is trending down. One patient was noncompliant and discontinued and patient #1 is compliant, we believe, but may be a true nonresponder as her BMI is not decreasing. However, as you've heard, she is perhaps the most challenging patient in terms of her underlying disease and her poorly controlled diabetes. And as we learn more, even stabilization, as Dr. Miller mentioned, for her may represent a response. Ultimately, body composition is measured by DEXA scans out to be a better measure of response. As we have seen with our HO trial, restoring signaling through the MC4R pathway seems to lead to significantly more fat than mean mass loss, which is what we would hope to see. Patient 6 is a good example where the BMI change did not capture the magnitude of the decrease in fat mass. Although the trial was not designed to formally assess hyperphagia, we are encouraged by the changes in HQ-CT scores, and we believe these scores reflect the fact patients are experiencing a change on treatment. In light of the disease severity of the first patients enrolled and the relative consistency of the results to date, we believe these data support moving to Phase 3 with confidence we can run a positive trial with primary and key secondary endpoints of BMI change, a responder analysis HQ-CT scores and body composition. Based on the biology of the MC4R receptor, we also believe that if we hit the BMI endpoint, we are likely to have a positive result on the hyperphagia scores. And for the next steps with setmelanotide, our plan is to complete this trial, get all 18 patients past the 6-month time point. We'll release the data at that point and then submitted a Phase III trial proposal to the FDA for review. We will aim to disclose the full 6-month data during the first half of 2026, as I noted, as well as at a medical meeting next year. Lastly, these data from the setmelanotide trial support our confidence that MC4R agonism is a biologically sound approach to treating patients with PWS. And with that in mind, we have added Part D to our ongoing Phase I study, open-label study evaluating 718 weekly specific MC4R agonist designed not to cause hyperpigmentation and will enroll up to 20 patients with each patient dose escalating from 10 to 40 milligrams as tolerated. We have the ability to go to 50 milligrams if needed. Our goal is to have that part of the trial enrolled by the second half of 2026. The Part C portion of that trial in HO patients remains on track to complete enrollment, as you know, in the first quarter of '26. With that, we'll open it up for questions. Operator?

[Operator Instructions] Our first question comes from Phil Nadeau with TD Cowen.

Congrats on the data. David, we wanted to dive into your comments about the Phase 3 trial and the likelihood of success in a bit more detail and kind of have 2 questions in that vein. So first, could you go into a bit more detail about what you think the primary endpoint of a Phase 3 trial would be? Would it be a change of -- change in mean BMI from baseline with the expectation that, that would hit a 5% hurdle? Or do you think the responder analysis could be the primary endpoint? And then second question, kind of along those lines, I guess, as we look at the data, it does seem like at least in 2 of the patients, the weight loss was progressive that gets you to that BMI of over 5% by month 6 and admitting there's mitigating circumstances for the 3 patients, but it wasn't necessarily progressive in the other 3. So how confident are you that the BMI reductions here could be progressive to get you to that 5% level by month 12? And are you thinking maybe in a placebo-adjusted trial, the placebo group would actually increase. So you don't need an absolute reduction of 5% in the patients, but placebo adjusted if you could get there anyway?

Yes. Thanks, Phil. So we're early. We'll -- again, as we said, we'll let this data mature and the results from the full 18-patient cohort at 6 months will help us answer some of those questions. But we made the decision and we're going forward to Phase 3 based on these results and obviously are thinking about that. I think the primary endpoint, again, let's get the 18-patient data, but it will be likely BMI percent change. And as you highlighted, and we've been clear all along that our goal is to get to a BMI reduction of 5% or more at 52 weeks. I think that's completely doable. I think the probability we can hit a placebo-adjusted 5% difference is extremely high. So -- and that is all we will need, FDA agreeing here, but that is exactly the way the regulation is written. The regulation is written is a 5% placebo-adjusted change. So if you look at the history of these patients, as Dr. Miller said, gaining weight coming into the trial, if you look at the fact that in the vast majority of patients, we are having a clear biologic effect with a reduction. And even in those who have gained some weight, there's a plateauing there, maybe a further decrease over time. So all of that gives me a lot of confidence that this BMI primary point percent change can be the primary endpoint, and we can hit it, one. Two, responder analysis is important for the regulators and FDA specifically. So that will very much be part of it. Just to remind people on BBS, we had about -- and that's another tough disease. We had about 60% of the patients who cleared 5% at 52 weeks. So it's not that, that specific indication at 100%. And so we have some history there with challenging populations. Third, the HQ-CT scores, again, in a placebo-controlled trial based as I indicated on the biology, I think that will be positive. And then, of course, body composition change, and we will get DEXA scans on all patients in our Phase 3 trial. So that will not be a primary, but that will be a key secondary. And in rare diseases, you bring the totality of the evidence to bear. It's not just a pure primary. I think we'll hit the primary for the reasons I said, but it will be supported strongly by the key secondaries.

That's really helpful. Maybe just one follow-up question. What change in BMI would you expect for an untreated patient similar to the ones that you enrolled in this trial over 12 months? How much is the average?

Dr. Miller, maybe just...

It's about -- it's actually the opposite direction. So it can be close to 5% in 12 months.

Perfect. That's very helpful. Congrats again on the data.

Yes. And to that Dr. Miller's point, I mean, that's supported by the data from the randomized controlled trial of beloranib that was run originally.

Next question comes from Tazeen Ahmad with Bank of America.

Thanks for the update on PWS. I wanted to get a sense about how you're thinking about the profile of patients you plan to enroll in Phase 3. So just based on the data that you presented today, you've talked about certain caveats about why certain patients may not have had ideal weight loss, for example. So how do you take that information and translate that into entry criteria for your study? And then as it relates to 718, you've chosen to look at it, is it primarily because it doesn't have the hyperpigmentation side effect? Or do you think it could have mechanistically reason to induce more weight loss and maybe more control of hyperphagia than you've seen with setmelanotide?

Yes. Thanks, Tazeen. Let me take the 718 question first. No, the -- a couple of reasons for proceeding with 718. One is we had an early sense that this drug was working. So we activated that plan because we had a vehicle here with the 718 study where we knew we could add a Part D arm, number one. Number two, I think between the weekly injectable and the daily oral, particularly because we didn't have our smaller formulation ready to go, concern about patients joking on a pill, for example, in a Prader-Willi population was more of a concern and the weekly seemed like a preferable approach there. Three, our goal for all of our indications is to get our next-generation programs approved for those. And so this gave us a running start by getting -- being able to get some information. So we're well underway here in terms of getting that arm activated. As I said, the first site has been initiated, and we hope to have our first patient screened by the end of the month. So all that was what went into choosing to go forward with 718. In terms of entry criteria, yes, that's -- it's a really important question. And again, what you've heard, and I'm not sure this is just such a complicated population. My initial response is it would be an all-comers trial. I mean one of the advantages is that we can enroll the patients that Dr. Miller highlighted who have no other option. And I don't think we would be looking to enroll a trial where we cherry picked a few patients. So I imagine an all-comer trial, patients with obesity, so we can see the change in their BMI. But remember, again, when you do an all-comers trial and it's randomized, those patients who end up in the placebo group, they'll drive the placebo change. And so with the primary endpoint of placebo adjusted, it will work fine in our benefit. So -- and I'm not -- I think as Dr. Miller also highlighted, severe diabetes, I don't think that's a major compounding problem for us and those patients have no other options. So yes, a long way of saying, I think it would be an all-comers trial.

Okay. And maybe just a quick follow-up. For PWS, if patients experience hyperpigmentation, do you think that this population is similar to how you described HO or doctors have described HO as that would not be rate limiting?

Dr. Miller?

I'm sorry, I was interacting with the patient. I apologize.

No, no. Yes, Tazeen just asked, how significant do you think hyperpigmentation is in this group? Yes, did have one patient...

Not at all other than that one patient. Yes, no, they don't care. Actually, they kind of like it because they tend to -- especially the deletion patients delete a pigment gene. And so they tend to be very fair skinned. And so the hyperpigmentation actually makes them color-wise more similar to their family. And I've had -- other than the one who discontinued, I've had 0 patients complain about it.

And our next question will come from Mike Ulz with Morgan Stanley.

Congratulations on the early data as well. Maybe just a question among those patients that had lost weight, can you talk about the pattern of weight loss over the treatment period? Was it more choppy? Or was there a general downward trend in those patients? And do you think continuing to treat those patients longer may result in even greater weight loss?

Yes. Dr. Miller, I'm going to ask to help here. I mean we did see choppiness, of course, and part of that was in a couple of the patients related to their diabetes and other meds, but what do you think?

Yes. I think it was a steady downward trend. Of course, there's always choppiness, but it's been sort of slow and steady, a pound or 2 a month, so -- which I feel is kind of a healthy way to lose weight. And it also tends to be more visceral fat than subcutaneous fat, at least on DEXA and looking at them, you can see an improvement in the fat that's accumulated around the abdomen, which is from a metabolic perspective, awesome. And so yes, I think, again, slow and steady. It's -- some of them are disappointed where there's a month where they haven't lost weight, but we're also at holiday season. And so people eat for different reasons besides hunger, too. So I'm going to try to tell everybody that slow and steady wins the race, but I do anticipate that by a year, we'll see more significant changes.

And our next question will come from Seamus Fernandez with Guggenheim.

Congrats on the data. Apologies for the background noise. Just wanted to quickly ask, in terms of the ability to evaluate not just BMI, it seems like there would also be the possibility of Z-score depending on the patients that get recruited into the study. So just interested to know, again, maybe along the lines of Phil's questions, the types of endpoints, how you think the agency is likely to evaluate the drug here? And then could you also help us understand how necessary the higher dose regimen was and the percentage of patients that reached the top dose and stayed on it?

Yes. Sam, let me just clarify. Your first question was about BMI Z scores as being an additional piece?

Yes.

Yes. So yes, for sure. So let me take that first. What we've done -- we'll do the same thing we've done in all of our trials. We don't -- in rare disease, again, particularly these groups, we don't have the luxury of running an adult only, adolescent only under 12 only. So we'll run one trial. It's likely to be as the entry criteria for this one are 6 years and above or 4 years and above, we'll see where we are. But -- so we'll need an endpoint that captures both. So BMI, of course, is better than weight. But BMIZ analysis will be done for those kids for the children who are under 18 years of age. And then our responder analysis will be similar to what we've done previously, which is to say how many patients cleared 5% on their BMI and for those under 18, how many had a BMIZ score change of greater than 0.2 clinical meaning. So those will be the -- that will be added, and it will give us greater insight and also mitigate some of the fact that BMIs do increase as kids are growing. Sorry, what was the other one was -- the dosing, how they've done in the dosing. So the majority of patients and Dr. if you're there, maybe you can just comment, the majority have been between 4 and 5 mgs, but Dr. Miller, maybe you can just comment on dosing.

Yes. I think there's only one patient that remains on 5 milligrams, and that's patient #1. And so most have hung out at 4 to 4.5 and seem to be doing very well with that -- sorry, I'm measuring waist circumference as we speak. And so they seem to be doing very well with that. Sorry. They seem to be doing well with the dose of 4 to 4.5 the episode of fatigue that was reported as one of the AEs was due to -- with somebody on the 5-milligram dose. These patients take a lot of medications, especially a lot of psych medications. So parents tend to be of the mindset that the smaller the effective dose, the better, which I don't disagree with. So we went up to 5 on almost everybody, but most of the people seem to do the best on 4 to 4.5. All the little ones under 12 are on 3 as a maximum dose and are doing very well on that. So yes, so it's not many that are on the maximum dose, but there's -- I would say, everyone, except for one over the age of 12 is above -- is at 4 or 4.5 milligrams, except for the one at 5 milligrams.

Okay. And then maybe if I could just ask one last follow-up. The percentage of patients that you think would be applicable just given your initial experience to treatment with either setmelanotide or a weekly 718 in this patient population, is it 50%, 80%, 100%, 20%? Just helpful to know how you're reacting to these data in those terms? I know it's a little bit of an unfair question.

It is a little bit of an unfair question because, of course, weight issues differ across different providers and where individuals with Prader-Willi live and environmental security and all that kind of stuff. I mean, honestly, if you look at people who would be eligible from if you just look at weight, for example, it's probably about 40% of the population that would be eligible. I would say if you're looking at weight and hyperphagia, it's probably going to be less than that. But yes, I still think it's a very -- a pretty significant proportion of the population.

And our next question will come from Derek Archila with Wells.

Congrats on the update. So just one for David, and one for Dr. Miller. David, I guess, should we assume that the start of this Part D cohort with 718 in Prader-Willi patients implies that Part C and HO is trending positively? And then a question for Dr. Miller is more centered around the Vykat and IMCIVREE combo usage in the trial. It didn't seem like there was much synergy there, but just curious to get your thoughts if there's any things underlying there. And I guess, whether or not you see roles for both Vykat and IMCIVREE in your practice?

Dr. Miller, why don't you take the Vykat first and then I'll answer...

Okay. So I definitely do think there's synergy. Again, you only saw data from one of the patients, but we actually have it evenly divided between those on Vykat and those not on Vykat who are in this clinical trial. And I think from a body composition perspective, I'm definitively seeing synergy between the 2 medications. And so, yes, the data is so early in most of those patients because, again, those 2 that you saw some data on were probably the most severe that we had. They were people that run multiple diabetes meds because the parents said that the efficacy of the Vykat was such that they would never come off of it, no matter how many additional meds they had to add. And I hated that for them because I would really like to not have people on a ton of different meds if we can avoid it. So anyway, so those were the probably the most severe of the people enrolled into the trial that were on Vykat. And I do anticipate a good synergy between the 2 drugs, if that answers your question. And yes, I think I would use both together in certain situations and clinics.

And just to be clear, the trial, as you know, wasn't designed to draw any conclusions about that necessarily. We obviously, as Dr. Miller said, very interested in seeing it. And we would envision a Phase 3 trial, which would allow as we're running this trial, patients on Vykat to be enrolled. And as we did with GLP-1s and our other study, they would just need to be stable coming into the trial on their Vykat dose. So background. And then your other question, Derek, was, is there any read-through to starting Part D to what's going on in Part C? And what all I would say there is what I've said all along back to before we even had the BIVA data, many of you often ask between the BIVA and the 718, which one do you think is more likely to be positive? I always answered that, that look, there's more unknowns around BIVA. 718 was built off of what we know about setmelanotide. It's much closer in terms of preclinical data and the like. And therefore, if you had to bet, I would bet that 718 would be okay. So anyway, there's no change to that opinion. We now have BIVA data, which looks very good. So that's sort of taken some of the uncertainty out of the part of the equation. But we're still optimistic about 718 and but I can't take that next step, which would say we did this because of what we're seeing in 718.

And our next question will come from Corinne Johnson with Goldman Sachs.

This is Anupam on behalf of Corinne. So basically, I have 2 questions. So one, like what can you share regarding the correlation between change in hyperphagia and change in body weight asking from this -- asking from a perspective that you would likely be using the change in BMI as the primary endpoint going forward? And the second one is like what else do you need to see from this ongoing study to inform the registrational trial design?

So let me say on the correlation, and I'm going to draw from all of our experience here. So across all of our development programs with MC4R agonism, we see a very consistent decrease in the hunger score. We've used this 10-point VAS scale. And literally, BBS, the PPL original study and of course, the HO studies, almost independent of where patients started on that scale. So most patients, for example, had scores in the 7 to 8 range. We had, on average, 2 to 3-point decreases. But even patients with a 4-point starting rating on that scale, they had 2- to 3-point decreases in there. So they were experiencing a change, number one. Number two, when we try to correlate that change with weight, it doesn't correlate per se. It moves together, but it doesn't correlate. It's not that the patient who saw a bigger change in their hunger score saw a bigger change in weight. And I think the same thing is true here in that biologically, and maybe that's part of what Dr. Miller is describing, these patients just feel better. Biologically, they're feeling an effect. How that translates into the specific tool you're using, in this case, in HQ-CT might be somewhat imprecise and therefore, a strong correlation in weight, as we've highlighted. Also, we don't have a pure weight test here in the sense that there's a lot of other factors these patients are dealing with, which may confound our ability to see the weight loss. So the long answer to say no, no correlation, but biologically, they do move together. And then your last question was what else do we need to see? No, we don't need to see anything else. As I said, in terms of making a decision to go to Phase 3, and that's why we're having the call today. I think we've made that decision. What -- the 6-month data in all 18 patients will give us is just a lot more color around how to think about planning that Phase 3. Obviously, 18 is double the amount of 8 here. So having more robust numbers is incredibly valuable. But we'll be looking for the same things we reported out on today.

And our next question will come from Dennis Ding with Jefferies...

Maybe a question on placebo. I know the beloranib data suggests placebo should gain BMI, but there's also a liraglutide study in kids that show placebo reduces BMI. So I wonder how you're thinking about the placebo effect and if there are nuances that we're missing with interpreting the liraglutide data? And then number two, for RM-718, it seems like you're looking at 10 to 50 milligrams weekly. How do those doses correlate with the doses of setmelanotide used here in the Prader-Willi trial? And could there -- could you guys be dosing higher?

Yes. So I can't -- I don't know if I can answer and Dr. Miller welcome any thoughts here. I mean the placebo effect, I think that beloranib data was a good randomized controlled trial. And so maybe it be about as good as it gets in terms of giving us some sense of what may happen here. I think currently, our experience in this trial is patients into this trial were gaining weight. So I'm not so concerned -- in our HO study is another example, if you have a defect in the MC4R pathway, you do not spontaneously lose weight. There's not a placebo effect. We didn't see it in our BBS trial. We had a different design in our PPL trial originally. And obviously, the HO patients, we had a 3% increase in the placebo group. So we can't answer your study exactly that, but I'm pretty confident that the placebo adjusted is likely to move in our favor. Dr. Miller, I don't know if you have any other thoughts there or...

I really don't. It is unusual to me that the liraglutide trial did show some reduction in weight at the 1-year point in the placebo group. But that's just not reality for the most part. For the most part, reality is that these individuals after age 7 to 8 to 9 start to gain weight, and it's very hard to go backwards and to lose weight, almost impossible.

Great. And then your question on the dosing for 718. So that trial is designed, they'll dose escalate from 10 to 40 mg. Your question was how does that relate to setmelanotide. So we don't have a direct 1:1. I mean the way we thought about -- I'll just go back to our original Camurus, which was the long-acting form of setmelanotide. When we ran that study, we did -- and this was not completely arbitrary, but we took a 3 mg dose and those patients crossed over to 30 mg and those who are on a 2 mg dose crossed over to 20, 7 days a week times 3 would give you 21 mg. So the idea here was to dose above the total amount delivered. That's been the strategy for 718 and going from 10 to 40 was to give us a little bit of cushion there because there was no reason not to. And still learning about weekly formulations and how that works in terms of translating to efficacy. The trial allows up to 50, and that's basically the same thought process as for this trial, which is almost all patients we've treated have done well at 3 mg. This was a new population with a lot of perhaps more challenging aspects to their disease. So we wanted to make sure dosing wasn't something left on the table. So we allowed dosing up to 5 mg in this case. So the ability to go to 50s, that's the same thought process. Does that help?

And our next question comes from Jon Wolleben with Citizens.

Just wondering if you had a chance to look at the PK data and if there's an association between drug levels and the effects you're seeing. And then pivoting to the Phase 3 trial, how do you think about the variability of moving to a multicenter study and kind of losing Dr. Miller's expertise, but perhaps getting less challenging patients at the same time. So how do you account for that moving into a larger multisite study?

Yes. I'll take that one first. I mean, yes, there's only one Dr. Miller in the world. I think that -- the beauty of larger placebo-controlled trials is the numbers basically take care of it. In theory, whatever variability you get site to site, investigator to investigator, that washes out in the randomized part of the trial. So I'm not actually not at all concerned about that. I do think your point that we will have a more representative PWS population than we have perhaps in these early patients we're describing today is based on the fact that these were Dr. Miller's most challenging patients with really truly no options. I think as the community sees results and becomes more interested, which is what tends to happen with drugs that look like they're working, I think we will get a broader population, and that should work to our benefit. So I'm not concerned, to be honest about that aspect of it. And with regard to PK values, we're collecting, but it's trough levels. So we won't be -- what it will give us is some insight into compliance and the like, but it's not -- we won't have tight PK curves that we can then try to translate to how that translates to efficacy, some sort of PD relationship. It will give us a sense, a, most importantly, are they taking the drug the way we thought. So that's it -- there's limitations here in terms of how much we could do with these patients.

And our next question will come from Whitney Ijem with Canaccord.

It's Angela on for Whitney. Congrats on the data. Just curious, any additional color you can provide on that one patient discontinuation? It sounded like hyperpigmentation was the reason, but was that the only reason? And then can you also confirm what dose they titrated to before discontinuing and like what the -- like the timing around that was?

Yes, I can answer those, Dr. Miller. So -- and this is based on feedback from Dr. Miller, I think there was a number of things going on too. These patients have -- it's not just the patient themselves, as I understand it. There's also potentially complex family dynamics, which can impact how a drug gets managed here. And maybe Dr. Miller, you want to jump in. The maximum dose they got to was 3.5 mg, but they were on and off, and they discontinued the study at 20 weeks. But Dr. Miller, anything else you want to add there?

I just chuckled when you said complex family issues because that's putting it lightly. Yes, no. And the 3.5, they were only on for -- I think he was only on for less than a week before she pulled it. So he was -- they were just extremely noncompliant. It was an adult patient who had never been treated with growth hormone or testosterone or anything. And so there was just a lot going on there with the mom having to give injections and she had her own stuff going on about that.

So yes, so that's it. So I think that you don't get to eliminate those patients are part of your cohort. But obviously, what we've looked for -- I'll just say this, in all of our trials with MC4 agonism and with a very simple concept that if you have a deficit in the pathway, you have a hormonal deficiency, we're replacing that hormone. And as with most hormone deficiency states, when you replace the hormone, you should have a very high percentage of responders. And I think that's what we're looking for here. And to the extent that somebody didn't respond, are there other issues? And obviously, in this case, there's definitely another issue.

Got it. And maybe a very quick -- sorry, if I could have a quick follow-up question for Dr. Miller. For the patients who might not be eligible for therapy on a weight basis, so about 60%, would you maybe want to put those patients on setmelanotide for other benefits like giving them more energy to do things or just be happier? Like is there a potential for a broader label here?

I am really -- I apologize. Can you repeat the question? Sorry, go ahead.

Sorry, just for the patients who might not be eligible because they're overweight, would you also potentially want to put those patients on for the other benefits like having more energy to do things and just being happier overall? Is there like just that potential for a broader label down the road?

I don't have the answer to that because every trial I've done with Rhythm through all the years, which are many. It's always been for patients who are significantly overweight. And so -- but yes, I do definitely across the board with this drug, see improvements in what appears to be improvements in mental health and physical health. So it's a very good question that you would have to ask Dr. Meeker the answer to. In my personal experience, I mean, I'm just honestly thrilled looking at the results in these patients, again, who I consider to be some of my most very difficult patients to control.

Yes. And Angela, I think building on what Dr. Miller said, we'll evaluate that population. We'll start with the BMI patients who have obesity defined by their BMI, but these other changes, if you correct the underlying biology, you can imagine a world where if they're not obese today because they're in a rigorously controlled environment, maybe this drug could help get them more freedom and not have to live in the exact same environment. And how you run that trial, that becomes interesting, and those are things we'll think about, of course. But we'll definitely start with those patients who are obese.

And our next question will come from Paul Matteis with Stifel.

This is Julian on for Paul. Congrats on the early data. I guess just when thinking about the Part D of the study, can you just remind us which sites are being used? Is it going to be Dr. Miller's and that one additional site that you enrolled that you've talked about in the past? Or any additional plans for that? And then when talking about allowing background Vykat for a future Phase 3, is there a cap or a proportion that you would target for enrolling patients on background Vykat? And if you have any initial thoughts on that would be great to hear.

Sure. So the question -- the answer on the Vykat piece is, I don't know, it's a good question. We'll see how the world evolves in terms of how many patients would be on Vykat in this population. Whatever we do, we would stratify. So you have an equal number in both. You do a subset analysis of patients on Vykat and not on Vykat. I think what's really encouraging about this data to date is the monotherapy, I mean, those -- we only have 2 patients here. The bulk of these patients in the first 8 patients are not on Vykat. We're seeing the same response at this point. So as Dr. Miller said earlier, we have a lot to learn about how these 2 drugs might interact together. But the good news for us is that the monotherapy is clearly active here and having meaningful -- what seem to be meaningful effects here on both weight and some of these other parameters. So that's the way we'd handle the Vykat. With regard to the sites in the Part D, again, this was, a, it made sense for us strategically; b, it was a bit opportunistic. So we have gone to the sites we're using for that 718 HO study. They're not all the same investigators at the site. So the other investigators may be following the Prader-Willi population. But in terms of getting the study up and running, that was the easiest. We're evaluating whether we'll add some additional sites. Dr. Miller site is pretty backed out at the moment. She's done an incredible amount for us. And so she may not be one of those sites, but she'll certainly be a lead investigator going into Phase 3.

And our next question will come from Thomas Smith with Leerink Partners.

Congrats on the early data. Apologies if I missed this, but could you talk a little bit about the kinetics and the consistency of the hyperphagia improvements in the study and maybe directionally how that's trending out at 6 months and beyond? And then on the Phase 3 plans, could you elaborate a little bit on some of the stratification factors you're considering, whether it's baseline BMI, hyperphagia genotype or some other factors and how you're planning to maximize probability of success there from an enrollment standpoint?

Yes. With regard to the kinetics of the HQ-CT, those scores drop quickly, meaning over the first 1 to 2 months, and then they stay down at basically that level. So we showed you the data from 3 months. That's very consistent with what we would expect to see biologically. It's what we've seen in all of our other trials. An extreme example of a BBS patient, which always sticks in my mind is the patient was dosed in the doctor's office, the first dose and the doctor got a call at noon time from the mother who said, we're at the airport and my son left half the sandwich on his plate and he's never done that before. So that's consistent with how the physiology of this MC4R agonism works. And so again, seeing this change in scores on the earlier side, again, makes sense to us. Now in Prader-Willi, it's complicated because you've got a lot of other behavioral issues, which may not be driven specifically by a lack of satiety. And so those things may complicate the ability to see changes in behavior and some of the things that are being captured by the HQ-CT. But in general, that's the biology. It moves quickly and tends to stay at about the same level -- with regard to Phase 3, again, I'll please just it's early here. I've given you some initial thinking. Things we've done in the past, which we would for sure do here. If we have an all-comers trial, age 6 and above, for example, we'd stratify by age. You have to stratify by age, stratify by things that have the potential to have a significant impact on outcomes. So the fact that Vykat, maybe there might be synergy, then of course, you want to stratify that. And then I think beyond that, you can have infinite stratification, we'll get some more data in here and make final decisions, but those are 2 that for sure, we'll stratify for.

And our next question will come from Rohan Mathur with Oppenheimer.

This is Rohan on for Leland. Just given how debilitating hyperphagia is in this patient population, how are you thinking about the relative importance of showing robust reduction in hyperphagia versus clinically meaningful BMI changes, especially as you're thinking about the pivotal study? And this is maybe more for Dr. Miller. As you think about positioning with Vykat, what kind of patients would you expect to be considered eligible for Vykat and not setmelanotide?

Let me take the first one, and then Dr. Miller, you can think if there's anything you want to add there? In terms of what we would view as most important, the way we think about BMI versus -- I mean, it's all part of what makes it's all part of the disease. If you have a deficiency in the pathway, it's not like you just gain weight necessarily without an impact on your satiety signal. Now like satiety like pain, patients interpret it differently. I mean in some patients, you run a pain score. It's not that the injury isn't there, whatever induced might induce pain, just people interpret it differently. Some have little to no "registry" of that, others find it extreme. And so this hyperphagia endpoint is no different than that. And so again, with that context, our focus will be on the BMI changes, the body composition changes. And the way we think about hyperphagia is biologically, if we are moving those aspects of the disease because the BMI, the weight gain, the BMI gain is a consequence of the lack of a satiety signal, i.e., increased energy intake and decreased energy expenditure and that combination, of course, leads to often the more obesity we see in patients with this deficit. So I don't know if that answers your question. But yes, BMIs are going to be our focus and associated changes there. But hyperphagia, if those move, it will move. And that's how we think about it. And Dr. Miller, just your thoughts in the world -- and again, I'm going to give you an out here in terms of being extremely early, but thinking about patients on Vykat versus something like a setmelanotide.

Yes. I mean I think I would do what I've done here, which is that I would choose patients for setmelanotide who weight and the comorbidities of weight are very significant problems for them, whether that be diabetes or lymphedema or untreated obstructive sleep apnea. For Vykat, it's been fairly easy to choose who goes on, people with significant hyperphagia go on. And just because you do have significant hyperphagia and Prader-Willi does not mean you have to be obese. Most of the families -- and we're talking a younger generation here right now. The older generation is still a little bit skeptical of any new drugs. But with regard to Vykat, the families -- I mean food is locked, there's constant supervision, that kind of thing. And so Vykat allows them to have a little bit more freedom and a freedom for the kids in their lives to live a more normal life. And so I'm choosing ones that are not having those complications that would potentially cause problems or side effects on Vykat if they were to start it clinically. And for setmelanotide, I mean, again, it would be the people that really are having complications of their weight because, again, weight is almost impossible to treat in Prader-Willi. It's very, very difficult.

Okay. Thank you for that question. I know we got to get Dr. Miller back to clinic here. We could take -- there's 3 more questions, please.

Yes. For the last 3, if we just ask to limit it to one question...

One question each, and we'll try to wrap up here.

And the next question will come from Raghuram Selvaraju with H.C. Wainwright.

I just wanted to ask about how you folks are looking at the prediabetic space in Prader-Willi syndrome. At what point would you be able to proactively identify patients who wouldn't be considered candidates for Vykat therapy because of the likelihood that the therapy might predispose them towards the development of diabetes. So what we're really looking at is the segment of patients who might not necessarily be formally diagnosed with type 2 diabetes, but who are trending in that direction. And maybe this, in a sense, is also something for the expert to opine on. But I just wanted to see if it would be possible for you to comment on how early in the treatment continuum you might expect a drug like setmelanotide to be deployable.

So I will say that sorry, go ahead, David. Sorry.

No. Go ahead.

I was going to say that prediabetes itself does not stop me from starting someone on Vykat. I mean, obviously, we watch the blood sugars very closely. We watch the A1c very closely. During the clinical trial, which I was one of the lead investigators for, we saw the sugars and A1c initially go up and then came back down and stabilized over time. So I advise the patients that, that's what happened in the trial. And as long as we stick to diet and we do what we're supposed to do, then I'm not really worried about starting them on Vykat. So that's not the population I'm really thinking of. It's the people who have overt diabetes. It's the people with an A1c -- I mean, patient #1 in this trial, her A1c was 15.4 when she came in. I mean, in patient #2, I think she was 12.1 when she came in. I mean those are people that just flat out would never be -- I would never consider for Vykat therapy. Those are the people I'm thinking about for starting setmelanotide versus Vykat. Does that answer your question?

Yes, that's perfect.

And the next question will come from Samantha Semenkow with Citi.

This is Ben on for Sam. I was wondering if you could provide -- or excuse me, if you could remind us or maybe provide some additional color on the differences in the patients that had deeper responses between months 3 and 6 versus those that didn't? And then how do you plan to control for those in the planned registrational trial?

Yes, I'll take it. We can't plan for that. But just to remind you, so out of the 5 patients who made it to the end of the trial, 3 of them trended down, 2 cleared the 5% that was patient 2 and 3. Patient 6, which I went through, that patient plateaued from month 3 to 6 on their BMI, but that was the patient with their DEXA scan that showed the 10% decrease in their fat mass. So I view all of those patients as good strong responders, nothing to do. And then patient #5, as we talked about, he had actually decreased 4% at month 2. Now it was month 3, he had already -- during that period in noncompliance, he had started to regain. So again, those kind of patients are incredibly helpful, which is they're an on/off. Looks like they're responding, they're taking the meds. When you stop the meds, they regain again. And so all you can do in a Phase 3 trial is you just try to maximize compliance as best you can. And then patient 1, we talked about a lot, which is just really challenging and maybe stabilization for her is already a win. And her corresponding phenotype in the placebo group would be continuing to gain weight. So that would offset. So that's how we think about that part of it.

And the last question will come from Joey Stringer with Needham...

Sorry if I missed this, but just generally, can you describe the types of background meds that patients were on? I know you mentioned ICAT, but others that could potentially affect weight loss such as CLIPS. And then quickly for Dr. Miller, just in general, were the patient baseline characteristics and the corresponding background meds representative with what you would see with PWS patients in your practice?

I can answer both questions actually, David, if that's okay. So the background meds, nobody was on a GLP-1. And so there were really -- nobody was on any med aside from Vykat VCA that potentially could even potentially have an effect on weight. The great majority of these patients are on atypical antipsychotics, which is very, very common in the population of Prader-Willi that we're looking at here. Adolescents, there's a very high incidence of people on atypical antipsychotics due to behavioral problems. And so that was the most common med. Growth hormone, of course, levothyroxine, occasionally Corteva for central adrenal insufficiency. Some behavioral meds like Depakote, Llithium for patients that had particularly severe behavior problems. Those were the most common. It was mostly psych meds that were the most common concurrent medications for people on this trial. And again, that is very representative of the population.

Perfect. And some of those meds can contribute to weight gain, so they do.

Right. Exactly, not weight loss, right?

Okay. I think that was the last question. So I want to thank all of you for tuning in this morning. Obviously, we're excited about where we are and really looking forward to developing further in this indication. Talk to you all soon.

This concludes today's conference call. Thank you for participating, and you may now disconnect.