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

Good day, everyone, and thank you for standing by. Welcome to Rhythm Pharmaceuticals Results from Phase II Prader-Willi Syndrome trial. [Operator Instructions] Please be advised that today's conference is being recorded. Now it's my pleasure to hand the conference to David Connolly with Investor Relations at Rhythm Pharmaceuticals. Please proceed.

Thank you, [Carmen]. I'm Dave Connolly here at Rhythm Pharmaceuticals. This morning, we issued a press release announcing positive interim data from our Phase II trial of setmelanotide in patients with Prader-Willi syndrome. That press release is available on our website. Also, our slides for this call can be accessed and controlled by going to the Investors section of our website at ir.rhythmtx.com. On the call today are David Meeker, our Chairman, Chief Executive Officer and President of Rhythm Pharmaceuticals; and Dr. Jennifer Miller, Pediatric Endocrinologist at the University of Florida. On Slide 3, I'll remind you that this call contains remarks concerning future expectations, plans and prospects, which constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual or quarterly reports on file with the SEC. In addition, any forward-looking statements represent our views as of today and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to David Meeker, who will begin on Slide 5.

Thank you, Dave. Good morning, everybody, and thank you for joining on a Saturday. We're thrilled to have Dr. Miller joining us this morning despite a 1:00 a.m. arrival last night. Dr. Miller will present the 6-month data results from our open-label study of setmelanotide in patients with PWS at an American College of Endocrinology poster session at 12:45 Chicago Time today. The headline is that we saw a consistent response to setmelanotide across four key measures. BMI and BMI-Z scores decreased with a corresponding decrease in fat mass while preserving lean mass, and we saw a consistent decrease in both their hyperphagia scores and their anxiety. These results reinforce the rationale and our conviction to advance MC4R agonism to Phase III in PWS. This morning, we will present the data that will be in the poster along with some additional color. Before we do that, I want to remind you of Rhythm's three key pillars on Slide 6, underlying our strategy of fully developing therapies for diseases defined by impaired signaling through the MC4R pathway. We will continue to work on genetic causes. We are pleased with the start of our launch into acquired HO. And as you will hear today, we believe we can make a significant difference in the lives of patients living with PWS. The epidemiology of PWS is reasonably well understood, and we did our own analysis following the methodology outlined on Slide 7. We estimate a prevalent population of 12,500 to 16,000 in each of the U.S. and Europe with 80% to 90% of patients having MC4R pathway impairment for a target population range of 8,500 to 12,750. In the appendix, there are a few slides that walk you through our bottoms-up methodology with citations. Now let's move to the data highlights on Slide 8. We are, as promised, showing you four metrics, which in their totality, we believe capture the full picture of the benefit of treatment with setmelanotide. This is a complex disease, characterized not only by the hyperphagia and associated obesity in patients who are not severely calorie restricted, but also challenging behaviors, including rigidity, obsessive compulsive disorder, a tendency to emotional breakdowns and in some patients, more violent behaviors. In addition to BMI in adults and BMI-Z in children, we record changes in their hyperphagia questionnaire for clinical trials, the HQ-CT score, the currently accepted hyperphagia score. The HQ-CT is a 9-item caregiver assessment with each item being scored on a 0 to 4-point scale with a possible maximum score of 36. The higher the score, the more severe the hyperphagia. In the FDA review of VYKAT, the agency's anchor-based evaluation of the study data found that a plausible range of clinically meaningful change thresholds in HQ-CT total score is between 4 and 7.5 points. The Prader-Willi Syndrome anxiousness and distress Behaviors Questionnaire, or PADQ, is also a caregiver-reported assessment with 14 items scored on a scale of 0 to 4 and a maximum potential score of 56. The higher the score, the more severe the patient's anxiety and level of distress. An 11 point or more reduction in score is considered clinically meaningful. As shown on Slide 8, the mean BMI decrease at 6 months across all 17 patients was 3.06%. Adult patients had a mean BMI decrease of 3.11% and the 7 pediatric patients some of whom experienced significant growth during the 6-month period had a BMI-Z score decrease of minus 0.35. The mean decrease in fat mass was 4.19% for the 16 patients with scans while preserving lean mass. And notably, 8 of 10 patients with moderate to severe hyperphagia, defined as a HQ-CT score of greater than equal to 13 had a 7-point or greater decrease in score. As a reminder, as shown on Slide 9, this is an open-label study of setmelanotide dosed up to a maximum of 5 milligrams as tolerated for a period of 6 months in patients aged greater than equal to 6 with PWS. Originally, this was a 6-month study, but we had amended the duration to be 1 year plus an open-label extension. The 6-month interim look at the data was prespecified. Slide 10 shows the patient demographics in disposition. A total of 18 patients were enrolled. Patient #4, as we indicated on our December call, discontinued the trial early for personal family reasons. All remaining 17 patients have stayed in the study, and that is the data we are presenting today. There were 11 adult patients and 7 patients less than 18. 7 patients had diabetes, 2 patients had extremely poorly controlled diabetes and 3 patients were treated with insulin, which can contribute to weight gain. 14 of 17 patients were treated with growth hormone, which has positive effects on body composition. The patients were living with severe obesity with a mean BMI of 39 overall and 41.1 in the adult patients. The mean BMI-Z score in patients less than 18 was 4.15. The average HQ-CT score was 12.83. As noted, a total of 10 patients had a baseline score greater than 13, a level that correlates with moderate to severe hyperphagia and that has been used in prior hyperphagia trials to define patient eligibility. The mean PADQ score was 29.9, a total of 9 patients were on VYKAT. Slide 11 shows the BMI plot for all 17 patients. 14 of 17 patients showed a decrease in their BMI over the course of the 6 months. The next 2 slides look at the BMI and BMI-Z score changes in adult and pediatric patients, respectively, with their corresponding DEXA scan results at 6 months below each patient. The dark blue bars represent the percent change in fat mass and the light purple bars show the percent change in lean mass. Beginning with the adults on Slide 12, you can see that 10 adult patients had a mean BMI percent decrease of 3.11%. Of note, all patients had a decrease in BMI over the 6 months with the exception of patient 1, who, as you remember from the December presentation had severe uncontrolled diabetes among other medical problems. Her weight has remained stable to down after her initial increase. If you look at the DEXA scan results shown below each patient, the 9 adult patients with an available DEXA scan had an approximate mean change in percent fat mass of minus 7.4%, with relative preservation of lean mass and in the majority of cases, the decrease in fat mass percent exceeded the percent decrease in BMI. The next slide shows the change in BMI-Z scores for pediatric patients. Importantly, most of these patients were on growth hormone. Mean BMI-Z score change was a minus 0.35 with reduction of greater than 0.2 being viewed as clinically meaningful. 6 of 7 patients had a BMI-Z score decrease of approximately 0.2 or greater. DEXA scan results must be interpreted differently in pediatric patients as they would be expected to add both fat and lean mass as they grow. Girls will add more fat mass than boys. Patient 5 did not have a measurable response to treatment, although his BMI has fluctuated significantly during the trial. The other patients showed a variable response on DEXA with both fat and lean mass decreasing in some and increasing in others consistent with their growth. Moving to the next 2 slides, we see the same BMI and BMI-Z bars at the top for each patient with the corresponding HQ-CT and PADQ scores for each patient on the two panels below. On Slide 14, we see the adult patients. HQ-CT scores decreased meaningfully in all 8 patients with elevated baseline values. Two patients had baseline scores of 0 with no opportunity to improve. And 6 out of 6 patients with scores greater than 7 and therefore, an opportunity to show a 7-point or more change all had a change of 7 or greater. The PADQ score results showed a similar pattern with all but 2 patients who had low baseline scores showing a decrease in their score and of the 8 patients with a baseline score of 11 or greater and therefore, the potential to show an 11-point or greater change, 6 out of 8 patients did show that change. Moving to Slide 15, we show the results for the pediatric patients. HQ-CT scores decreased in 5 out of 6 patients with baseline elevated scores, and they decreased by more than 7 points in 3 of 5 patients with baseline values greater than 7. Patient 5 did not show as noted, a clear clinical response on any of the 4 clinical assessments. And again, the PADQ results showed a similar pattern with 6 of 7 patients showing a decrease in their scores from baseline and 4 of 7 patients a greater than 11-point decrease. Patient #8 missed by 1 point on both the HQ-CT and PADQ measures from reaching the 7- and 11-point thresholds, respectively. On Slide 16, we show the safety results. The drug was well tolerated with most patients being on 4 or 4.5 milligrams. Injection site reactions and hyperpigmentation were most commonly seen. I would now like to move to Dr. Miller and ask her a few questions before we go to more general Q&A. Dr. Miller, thanks for joining us today.

Thank you for inviting me.

I want to acknowledge all the work you do for the Prader-Willi community. You have participated in most of the clinical trials which have been run in this population. And as we at Rhythm have come to appreciate, these are very challenging trials to conduct.

Thank you Dave.

My first question is just in general, what do you see as the most meaningful results to date in this study?

So I think the most meaningful results to date are the fact that everything is moving in the same direction. There is consistency across all of these measures between weight, BMI, DEXA results as well as HQ-CT scores and PADQ scores. So that's very positive to me.

Most patients seem to have a relatively consistent response to treatment across the different outcome measures with the exception of patients 1 and 5. And I know we discussed these patients on the December call, but can you remind us a little bit of sort of who they are and what was challenging about these patients?

Yes. So patient 1 has uncontrolled diabetes, very poorly controlled diabetes with an A1c that's ranged between 14% and 15% during the course of this time. She's noncompliant with diabetes medications. I insisted that mom be the one to give her the setmelanotide for the trial. I'm not sure of the consistency there either. But I mean, she and her mom both report that even though her weight has not decreased as they hoped that she seems happier. She's moving more. She's actually going out of the house and has a job now, which she wasn't doing prior to the trial. So they are actually quite thrilled with the results, even though she has not had an improvement in weight or BMI or DEXA scan. And again, I don't know if that's compliance or something else. And then patient 5 had a very difficult social situation, a lot of traveling, moving, -- he was in high school, where people were giving him food, no one was supervising. And so it was just a tough time during the course of this time because there was so much social upheaval within his life. And so -- but again, parents are very pleased. Both of these patients remain on drug and remain on the trial because both parents perceive a benefit. It may not be the benefit that you and I wanted to see and the benefit in terms of BMI and weight and HQ-CT score, but it is a benefit. And there -- both patients are consistently seeming happier, having less meltdowns, easier to deal with. And when they do have meltdowns, they are certainly shorter lived.

And I remember the patient #1 gained their weight immediately, pretty quickly coming into the trial by month 3. And since then.

She's been stable. Since then she's been stable. She's gone down gentamicin, but for the most part, she's been stable. She was never stable before. I've known her whole life. So this is the first time we've seen stability in weight gain. And so I do actually think that's a win.

Right. And it looks like she did have a decrease in her HQ-CT [ C20 ] baseline. So and then if you said patient 5, perhaps representative of just some of the challenges...

Yes. Absolutely.

Can you talk a little bit about factors which may cause visit-to-visit fluctuations despite a general trend towards improvement?

I mean I think there's a lot of factors that can cause visit-to-visit fluctuations. I mean, travel, of course, being a big one. We were having these people come every month. They're coming from all over the country for this trial. So travel is stressful and people tend to eat not normally when they're traveling. There's a lot of constipation within this population that worsens with travel, a lot of edema, particularly peripheral edema or lymphedema, which worsens with prolonged travel. So I think all of those factors contributed to weight fluctuations, how bad their edema was, whether they had used the bathroom regularly, that kind of stuff. And then I also think that things like school situation, school holidays and new teachers and things like that, of course, play a big role in variations from visit to visit. And unfortunately, we've had several families during the course of this trial that the parents have gotten profoundly ill, and that also has affected this because if the primary caregiver is not available to really be the one making sure that everything is happening the way that it should, you can get some variability in results.

So how would you characterize the patient population as compared to the broader Prader-Willi population, knowing that some of the more challenging patients are referred to you, and I know we've gotten this from a number of people who follow Rhythm.

Yes. I mean these were the worst of the worst patients for me. They were patients -- sorry, as I said, in December that did not qualify for any other treatment that we had tried everything else on. And I felt like I was at the end of what I could do. And so that made this a particularly challenging population to deal with being that they were so severe, their BMIs were so severe, the behaviors were so severe. And so I do think they are representative of a subset of some people with Prader-Willi syndrome. I don't think they're entirely representative of my whole patient population by far, but they definitely are representative of a big subset of people with Prader-Willi dealing with obesity, uncontrolled diabetes, hyperphagia, that kind of stuff.

They speak to the huge unmet need.

They do speak to the huge unmet need.

Can you talk a little bit about what you would expect to see in a placebo group with regard to changes in [ HQ-CT ] scores and the fact that they're been in a trial, what impact do you think that has?

I honestly don't think it has any. I mean at the beginning, for sure, I know that there is a very strong placebo effect in Prader-Willi. We've documented that in multiple trials. However, this far out, that placebo effect is gone. And so the fact that these results have remained consistent over at least 6 months and for some of these patients now 12 months is really encouraging to me. I think placebo is going to show nothing. I mean I think by 6 months in, you should see no changes, if not increasing -- well, you should see increasing in weight and BMI, increasing in body fat as is typical for the natural history of the syndrome. and behaviors in hyperphagia should not change.

Great. Last question. Now that we are 6 or more months into the trial, what is the general impression of the patient and their family with regard to the changes they've seen on treatment?

Everyone is really thrilled, very thrilled. As I said, all 17 patients have remained in the trial, which is remarkable considering how much we were asking of them during the trial. They are happier in terms of -- most of them, especially about the weight control and hyperphagia changes that they're seeing. But the other big piece of this is that the kids and adults are actually becoming more physically active, like they're choosing to become more physically active, and that's huge. They're purposely going out and doing stuff. Some of the adults have gotten jobs, which they weren't doing before. Parents report that in situations where their kid would normally have a meltdown because things didn't go their way, they're able to sort of reason their way through it and not have meltdown. And it's been quite remarkable. The behavior changes and the positive mental health changes that we've seen have been consistent across everybody. Some of these individuals have even been able to come off of their -- some of their -- not all of them, but some of their atypical antipsychotic meds or come down on those medications, which is huge as well because people with Prader-Willi, as many people know, are just polypharmacy at the extreme. So it's nice to see that we have some mechanism to improve quality of life in this population.

Great. Thank you. I mean it highlights again that no one measure captures the benefit here in terms of... Okay. So just to wrap up. So thank you, Dr. Miller, for that. And in summary, I'll start by acknowledging this trial has limitations. It's a small open-label data set. However, as you've heard, we're pretty excited about the results to date. All 4 measures in the majority of patients improved, which is strongly validating in terms of overall clinical benefit. The magnitude of the mean BMI change in adults was modest, but let's put that in some context. The best data to date historically in Prader-Willi, as we discussed on the December call, has been the Beloranib data. As shown on Slide 18, you can see the weight decrease at 6 months of 4% to 5% in the low and high dose groups, respectively. The HQ-CT results showed a 6- to 7-point decrease on average. Importantly, the placebo patients gained, as Dr. Miller highlighted would be expected given the natural history, gained 4% in weight. The HQ-CT results in the placebo patients showed an initial change consistent with the placebo effect, which had returned to baseline at 6 months, suggesting that any placebo effect was gone by that time point. Despite the absence of a control group, our results compare favorably with the results shown in that trial. When you factor in that the Beloranib study was only in patients greater than equal to 12 with a minimal HQ-CT score of 13 or greater and excluded patients with uncontrolled diabetes, for example, including those requiring insulin and that only 40% to 45% of the patients were on growth hormone, that trial may have selected for a population more likely to see weight change and improvement in HQ-CT. So in summary, what do we know? We know that the MC4R biology is part of the disease. The improvements in BMI and BMI-Z, the consistent or even more pronounced decrease in fat mass -- the consistent clinically meaningful improvement in HQ-CT, particularly in patients who had baseline scores greater than 13, accompanied by corresponding improvements in the anxiety distress scores are highly validating for a meaningful improvement in the disease. There's a reason these patients want to stay on treatment. So these results, number three, were observed in a potentially more challenging Prader-Willi population than may have participated in some of the earlier trials. And four, finally, the data strongly support moving to a Phase III program with confidence that we can achieve statistically significant and clinically meaningful results on both hyperphagia scores and weight-related measures. So with regard to next steps, as previously discussed, we will proceed to Phase III clinical trial with a final decision as to which therapeutic agent to be made later this year. We have received many appropriate questions on our development strategy. We started the Prader-Willi program believing the MC4R pathway is central to the hyperphagia weight gain seen in Prader-Willi. That has been confirmed. The recent VYKAT approval for hyperphagia establishes a pathway for approval, which is more efficient, 4 to 6 months in duration than a weight loss trial of 52 weeks. We can imagine running 2 trials, one focused on hyperphagia with weight and DEXA results as key secondaries and a second focused on BMI/BMI-Z endpoints with DEXA and HQ-CT scores as key secondaries. These plans will all be finalized, further finalized after discussion with the FDA. With that, we will now open the call up for general Q&A.

[Operator Instructions] comes from Tazeen Ahmad with Bank of America.

So I wanted to ask about the evidence that you're seeing of continued improvement over time. So can you help us get a sense about what the trajectory of weight loss has been, let's say, from month 3 to month 6? And I'm asking mostly because it seems like physicians want to see something around 5% more -- 5% or more in the range of weight loss -- sorry, or BMI reduction for these patients. So that's a question for both David and Dr. Miller as well.

Yes. Thanks,. Yes. So this is not HO, and I think we all got a little bit spoiled there with HO given the dramatic and profound ongoing response in that setting. So your first part of the question was what's the general pattern? The pattern is down. So the mean at 3 months was about 1.5% decrease and the mean at 6 months was 3%. And as I think most of you know on the call, I'm not a big fan of mean values in very small data sets because a small number of outliers can skew all that. But the general pattern is very clearly down, albeit at a much more gradual overall pace. And then -- I'm sorry, what was the other part of that?

The 5%.

Oh, the 5%, yes. So the approval here, this is very clear. And I think given the Prader-Willi is not general obesity, it's not HO, the regs as we have highlighted on previous calls and answering this question is a 5% placebo adjusted. And so at 3% at 6 months and with a -- if you use a 2% to 4% increase in a placebo group, which would seem to be very reasonable, and I ask Dr. Miller to comment on that, I think the possibility that 52 weeks, we could clear a 5% placebo-adjusted change in weight is extremely high. But I'll -- one last thing before I turn it over to Dr. Miller, rare diseases, approvals, regulatory reviews are about the totality of the evidence. You don't rise and fall on one single measure. And given the unmet medical need here and the consistency across results, again, I think we'd be very well positioned to make a strong case for the clinical benefit here. But maybe...

No, I 100% agree. And I was going to say something very similar because right now, we don't have anything that can get BMI down at all other than severe food restriction, locking people up, locking their kitchens and refrigerators, putting them in special institutions where they're on a 600-calorie diet. Those are not sustainable nor feasible solutions. This offers a sustainable solution with a continuing decline in BMI and BMI-Z. And so I actually view this data as really positive. I also got spoiled by HO and wanted to see more than a 5% loss, but it was slower and steadier in Prader-Willi syndrome, and people are happy with that. The parents and the individuals themselves are pleased with the results.

[Operator Instructions] It comes from the line of Phil Nadeau with TD Cowen.

Congratulations. The consistency in particular, is really impressive. Dr. Miller, you made the comment that this isn't a typical Prader-Willi population. It's maybe somewhat more severe than normal. We're curious how you think the results would therefore trend in a more normal population. I guess we could see it going either way in that maybe they're easier to treat, so you see bigger BMI and hyperphagia reductions or the opposite, if there's less room for improvement, maybe there's a ceiling effect. So curious to get your thoughts on that.

Yes. I think you're right the first time. I think actually, they'll probably be a little bit easier to treat. And so you'll likely see more profound effects of the drug than you are seeing in this population. Again, these are sort of my worst and my worst. I do think these represent a very significant subset of individuals with Prader-Willi from across the country and across the world. These individuals are not unique in any way. They're fairly unique to my patient population in that they are the worst of the worst for my patient population. But overall, these are fairly common problems that we see with Prader-Willi syndrome around the world. So -- but I do think if we include people that are a little bit more mild, the effects will be even more dramatic.

Our next question is from Derek Archila with Wells Fargo.

Congrats on the data. Just to your comments, David, as we think about the development plan for potentially maybe 2 trials or 2 different types of trials, I guess, how do you anticipate maybe different enrollment criteria? It seems like HQ-CT of greater than 13 for a 6-month trial seems very reasonable. But for a 12-month trial maybe focused on BMI, would you expand criteria beyond greater than 13 HQ-CT? Or would you have some sort of BMI baseline criteria? That would be helpful to know.

Yes. I'll let Dr. Miller chime in here. But initially, yes, so to run the HQ-CT without as a primary endpoint, by definition, you do -- we do what everybody else has done, which is restricted to patients who have a certain level of baseline severity. I think if you remember from the VYKAT, they even stratified for level of severity above the 13. So -- and those -- the higher you are, the worse you are, the greater the opportunity to improve if you have a drug that's actually working there. I think it's an interesting question on the weight trial. And to be honest, we haven't gotten any feedback from the FDA. And in these kind of diseases, I'm quoting you what's sort of generally required for weight loss trials and what we've been asked for some of our other indications. But we'll see if we need to do a full 52-week trial. I would go in again and just make the case that, that may or may not be what is in the best interest of patient population. But if we do, and that's the primary, then yes, you might want to open it up and not restrict it only to patients with an HQ-CT greater than 13 because there's clearly patients who have an unmet need will have lower scores than that. So...

I agree. I agree. And patients that are on VYKAT are going to obviously have lower HQ-CT scores coming in, but many of them still are suffering from obesity and metabolic consequences of obesity and behavior stuff. So I think this drug represents a really nice adjunct therapy to that. And so David and I have had some discussions at length about whether or not HQ-CT should be the primary endpoint for weight, BMI, DEXA scan. And so hence, the discussion of possibly doing 2 different trials to see to sort of pull out all that information from this population.

Our next question comes from Seamus Fernandez with Guggenheim Securities.

So just wanted to get a sense of if you have a robust sense of the compliance in this trial. It seems like if there were compliance challenges, once weekly could have a meaningful incremental benefit and probably be quite a bit easier to track from a compliance perspective in the actual clinical study. So just hoping to get a better sense of your tracking of the compliance in this patient population given some of the variability.

So overall compliance was excellent. People with Prader-Willi have a lot of compulsive tendencies, and they like to take medicines. And so having a daily injection was not a big deal for most of them. And they also -- many of them, as David mentioned, are on growth hormone. So they were used to already having a daily injection. It didn't bother them. The 2 that we suspected more noncompliance in #1 and #5, again, both were in difficult family situations. And patient #1 was on a once-weekly GLP-1 at one point in time, it didn't do much of anything for her mostly because she didn't take it because she didn't remember once a week to take it. And so once a week tends to be challenging for this population more than you would think, especially more than the general population because they like to do things routinely. And so having the routine of doing something daily actually works for most of them.

Our next question is from Corinne Johnson with Goldman Sachs.

Congrats on the data. I guess one question for me, Dr. Miller. You mentioned that these patients are seeing improvements in behavior. I guess what do you attribute those behavior changes to? Do you think it's a direct mechanism of the MC4R agonism? Or is it a result of the broader reduction in food noise?

It's a very good question, and I don't know the answer. We did also see it in the HO population as well and the genetic obesity population. People reported similar things. So it wasn't really surprising other than it was surprising to watch it happen. People -- again, the people that were in this trial were very, very severe, first few months of the trial, throwing things screaming, yelling and watching that improve was stunning. And some of the parents really are just beyond thrilled with the changes in this. And they said, I didn't like my child for a while and now I like them again. They're easier to deal with. And so I don't know the answer. It's the long and the short of it, but it -- it was kind of consistent across all the setmelanotide trials we've done. And so it leads me to believe it's something about the drug itself or the agonism of the melanocortin-4 receptor that does this, but I did find it really exciting and nice to see happen.

Yes. Maybe to that point, just you said you and I have talked about this. I mean the HO population, this increased desire to do things, be active, call it energy, whatever, didn't seem to tightly correlate with weight. It wasn't that they've been and are feeling better.

Right, exactly. And we saw behavior changes there, too, in a very positive manner as well. So yes.

Okay. Next question?

And it comes from Mike Ulz with Morgan Stanley.

This is Rohit on for Mike. Just based on these results, can you talk about the bar for results at 1 year? Is it still greater than a 5% reduction? And have you had any additional discussions with the regulators?

Yes. So just to be clear, we haven't had any discussions with the regulators. What I've repeated and I feel pretty confident because, again, those are the regs that if 5% placebo adjusted is the bar in terms of decreasing BMI or decreasing weight. So -- but I do, and I'll say it again, this is the kind of setting where it's a totality of the evidence that regulators will look at. And so it's very important, and that's why we've highlighted on today's results, what makes us very excited about this setting is how consistent the results were. It wasn't that we got a little bit of movement on BMI and not much else happened. No, we had directional improvement across all 4 measures. And I think as Dr. Miller highlighted, that's pretty meaningful and the behavior assessments are a big part of that. So yes, I think the bar, that's the bar for 52 weeks.

And the next question is from Samantha Semankov with Citi.

This is Ben on for Sam. Just curious, are you seeing any early patterns in age or HQ-CT or PADQ that might differentiate the patients that responded stronger in the study?

Yes. I mean I'll go first, and Dr. Miller can tell me if this sounds right. I think for both of those, they tended to move relatively quickly, the HQ-CT score and the PADQ. Now to the point that you see placebo effects early on in Prader-Willi, that initial movement, you wouldn't know was that a placebo effect or not. What gives us confidence is that, that initial move has really persisted. I mean it hasn't even drifted back essentially in all the patients. I mean it's held at that initial drop. And that, again, is very consistent with what we've seen in the other populations we've treated. Bardet-Biedl syndrome for 16 weeks, we saw the drop in the hunger scores and then it just maintained and HO similarly. And so it wasn't that these scores don't tend to go down over the course of a year. They tend to get the effect and then that effect persists. But...

I think that's correct. That sounds correct. I would say I do think the effects on increasing movement in physical activity on purpose that they're choosing to do more physical activity happens at about 3 to 6 months. We start to see more of that. So I'm very curious to follow these results out to a year because that should result in more meaningful changes in BMI as well.

Our next question is from John Wolleben with Citizens.

Just one for Dr. Miller. I'm wondering which one of these measures do patients and or parents care most about?

Honestly, behavior. I think that's a big one. Of course, weight and BMI are very important to them as well. They love seeing the results of the DEXA, like when we get DEXA, they're very excited to go and see those. So I mean, there's a lot of things. I think these families, all of them have been through a lot with hyperphagia and various hyperphagia-related analysis measures. And so I think that one is not quite as important to them as the changes in anxiety, behaviors, temper tantrums and body composition. But again, I think the biggest thing for everybody is quality of life. I think quality of life dramatically improves, and that's remarkable.

Yes. And John, I just want to highlight again, I think as Dr. Miller said, that's clearly what patients may value. We haven't had questions yet to date or so far on the call about the DEXA scans. But that's the other piece of this, which I think we -- I found really compelling here is that body composition is improving and the percent decrease in the fat mass, which was really consistent. And some of the variables Dr. Miller highlighted that may impact the measurement of a weight in BMI, like edema, water shifts and the like, constipation. I mean those are transient measures, but they impact how you measure those. The DEXA scan is a more reliable assessment of what's changing. And again, directionally and meaningfully, that fat mass was going down with, which is what we've seen in our other trials with setmelanotide, relative preservation of the mass. So, Next question.

Our next question comes from the line of Paul Matteis with Stifel.

Congrats on the data update. One question on the next steps on the trial side. David, are you thinking that you might try to pursue a randomized withdrawal study given that, that was a path for Soleno and just given the history of those studies having a higher POS? And then one quick question for Dr. Miller. When you think about this mechanism, does it make sense that weight loss would continue to build and be linear from month 6 to 12? Or would you think that most of the benefits would have already accrued on BMI by month 6?

So would we do a randomized withdrawal? I think the -- Dr. Miller is shaking her head. I think if you remember, as I understand it, again, just reading with public in terms of the VYKAT trial, that ran into the COVID situation. And so there are some unique aspects of that whole setting, and they end up negotiating a randomized withdrawal with the FDA. But no, I think we just run a straight-up trial, and I think this data would support the fact that we'd be able to see a meaningful difference there. And maybe Dr. Miller, just on from month 6 to 12.

Yes. So I think it's -- we've had what 5 patients complete 12 months now, and the trend has continued in terms of weight loss over that time. So I expect it to continue to build and to continue to improve.

Just to be clear on that, we haven't released the 5 patients.

Sorry.

But the -- in that 5 are the patients # 1 and 5. So -- but the other 3, to your point, have continued to trend down in patients 1 and 5, their situations are stable. So, next question.

The next question comes from Joseph Stringer with Needham & Company.

Apologies if I missed this, but how many of the 17 patients at 6 months titrated up to the 5 mg level? And on average, how long was that titration period? And then for Dr. Miller, assuming for now that the go-forward option in Phase III is the setmelanotide once-daily injection. Can you compare and contrast this with oral VYKAT in terms of balancing benefit and convenience in a real-world setting?

Maybe just on the dosing here and Dr. Miller can chime in. I think a significant percent of the patients did get up to 5. I think where, as I understand it from Dr. Miller, the talking to the families, they sort of settled out in the 4 to 4.5 milligram range at the point where they feel better, but I don't know.

That's correct. I'd say the great majority on 4 to 4.5, 5 didn't seem to do much above 4 or 4.5. So in the spirit of less is better, we went down on the dosing because it was -- if all things being equal, I'd prefer to give a lower dose to have less risk for side effects. The question about the once-a-week setmelanotide versus VYKAT is very difficult for me to answer because I don't know the answer. Again, I know that people with Prader-Willi do well with routine. So compliance with VYKAT tends to be excellent in the clinical population with a real-world situation because it's a once-a-day pills that they take and they like to put things in their mouth, but that works. But we haven't really -- I haven't really had a lot of experience with once-weekly either growth hormone or even the GLP-1s, which we do not use very commonly in Prader-Willi. Simply because the once-weekly growth hormone is not FDA approved for Prader-Willi syndrome. And so we don't very often get insurance approval, so we use daily. So I just don't have a lot of experience with once-weekly injections to know the level of compliance at this point in time.

Great. Next question.

Yes. It comes from the line of Lisa Walter with RBC.

Congrats on the data. Maybe one for Dr. Miller. In your experience, for a patient not on treatment, what is the average BMI gain likely to be in adults over 52 weeks? And do HQ-CT scores also change over time as well? And -- maybe just one for David. On your Phase III plans for Prader-Willi, are you going to move forward with setmelanotide or RM-718? Any color here would be helpful.

I'll take first. Yes. So in general, adults with Prader-Willi tend to gain around 3% BMI per year. That's pretty average. There's some variability there. It can be more, it can be less depending on environment. Of course, if they're in a group home where everything is restricted, obviously, that's not the situation. But in free living adults with Prader-Willi, there is a consistent gain in BMI through each year. And so that's what I would expect to see. What was the second part of the question?

So I'm just curious, actually, and I haven't talked about it specifically. As the Prader-Willi patients get older and become more challenging just physically to manage, that in a home setting, does their weight tend to go up more quickly?

Absolutely, it does. And also, they become more sedentary, their parents are getting older. They're tired, the families are tired of doing this. And so there's not as much pushback about the food and about the exercise and that kind of stuff. And so things just tend to spiral in a very negative way in general. Yes.

Which makes the results we saw in the adults even more...

Even more -- exactly.

Okay. And Lisa, I think your last question was just on which drug are we going to use? And I apologize for still kicking this out because we can obviously use setmelanotide, approved drug, and we've got this data now. And as I said many times, all things being equal, we'd love to do it with the next generation. You've heard some thoughts from Dr. Miller on the pros and cons of a weekly versus a daily. Bivamelagon is obviously a daily oral. So those are all considerations. So we'll make a decision by the end of the year or later this year and put a date on it, but all three things are still under consideration.

Our next question comes from Raghuram Selvaraju with H.C. Wainwright.

I guess these are both really for Dr. Miller. When you think about the possibility of combining a drug like setmelanotide or like 718 with any existing component of the PWS armamentarium? What kind of factors are likely to most affect your decision-making process there? Is it likely to be primarily the safety and tolerability profile or the additive or possibly synergistic efficacy that you might achieve there? And then also, maybe could you comment on the specific PWS patient subpopulation for whom, for whatever reason, primarily related to safety, perhaps a drug like VYKAT XR might be contraindicated and how likely those patients might be to be candidates for therapy with a drug like setmelanotide or 718?

Those are exactly the patients that I want on setmelanotide are the ones that have medical contraindications to going on VYKAT for the reasons of type 2 diabetes, severe obesity with edema already existing so that the risk profile of VYKAT would be exacerbated. I think the answer to your first question is actually both of those things. I think one of the things that I look at as me is the additive effect of multiple drugs. I like that idea. And mechanistically, it makes sense with VYKAT and setmelanotide that there would be a synergistic effect of those drugs. And then -- but I also, of course, look at safety and tolerability. One of the things that I think is the most challenging for most peds endos who take care or even adult endos who take care of people with Prader-Willi is that the polypharmacy with psych drugs is humongous. And many, many, many, many, many adults are on atypical antipsychotics, which, of course, worsen the metabolic profile and the weight gain and the risk for type 2 diabetes. And so having something like setmelanotide in the armamentarium that you could potentially lessen those risks is huge. And like I said, we saw one person come off of their atypical antipsychotic completely during this trial during the 6 months. And we've seen several reduce their doses quite significantly. So that alone, I think, is huge for me because those medicines are kind of the bane of my existence in terms of being an endocrinologist, but are necessary in terms of controlling symptoms for patients with Prader-Willi. So I think that -- again, I think that both factors would come into play, both safety and efficacy, but also the potential additive effects of more than one drug. And then lastly is the effects of maybe ameliorating the consequences of a drug that's necessary for a different reason.

And our last question comes from the line of Leland Gershell with Oppenheimer.

Great to see these positive data. I wanted to ask a question on dosing. I think, Dave, you had mentioned that these patients have gotten up to, I think, 4 to 4.5. And I think the -- up to the maximum potential was 5 per day. I wanted to ask Dr. Miller, do you think that there would be room for greater efficacy benefit with a more selective MC4R? I guess if we look at the table on 16 of the AEs, are we hitting adverse events that are preventing patients from getting dosed further? Do you think there might be room for greater efficacy in PWS with a more ideal melanocortin?

Yes. Thanks, Leland. Maybe I'll lead off here and then let Dr. Miller comment. So setmelanotide is a highly specific MC4R, it hits MC1, but it has very good potency at the MC4R receptor. It's about tenfold more potent than the endogenous ligand alpha melanocyte stimulating hormone. And so we've been pretty convinced that it's not clear there's a lot of room to do better in terms of pure MC4R agonism. And so back to why did we go up to 5, and we've done most of our work, as you all know, between 1 and 3 milligrams is the dosing regimen that's the approved regimen. We have safety clearance and tested as high as 7 mgs in patients with -- or normal volunteers with no problem. So going to 5, the goal there was to eliminate any possibility that we had left some efficacy on the table by not going high enough. And I think this trial has gone a long way to giving us some reassurance that we're in the right range. And the last thing I'll just say on the safety, what again is very reassuring is they seem to tolerate it well. So there weren't any unique safety issues going to the higher dose, but...

Yes. And like I said, I -- when people went down from the 5 down to 4 or 4.5, it was mostly just because they didn't perceive any additional benefit from being on 5 versus 4 or 4.5. And so they -- I've taught all patients that we don't want to put more stuff in your kids body than you have to do. So we -- if they didn't perceive any efficacy over a couple of months on 5 milligrams, then we would bring their dose back down to 4.5 to see how they did. And then if they still said, I think we were about the same on 4, we would bring it down to 4...

And this concludes our Q&A session. And I will turn the call back to David Meeker for closing comments.

Yes. So thanks again to everybody for tuning in. Hopefully, you're as excited as we are. Again, it's a tough population, but really encouraged by this initial data set and look forward to updating you on future progress on the program. Thanks all.

Thank you. And this concludes our conference. Thank you for participating, and you may now disconnect.