Good day, and thank you for standing by. Welcome to the Rhythm Pharmaceuticals Top-Line Results from Phase II Trial Evaluating Bivamelagon in Acquired Hypothalamic Obesity Conference Call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, David Connolly, Head of Investor Relations and Corporate Communications. Please go ahead.
Thank you, Shannon. Good morning, everyone, and welcome. Today, we issued a press release with the highlights from the positive phase II top-line results for bivamelagon in hypothalamic obesity. You can access the press release as well as the slides that we will be reviewing today by going to the investor section of our website. David Meeker, Chair, President, and Chief Executive Officer of Rhythm Pharmaceuticals, will present these data this morning, and Hunter Smith, our CFO, and Al Garfield, our Chief Scientific Officer, are 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 factor section of our SEC filings. In addition, any forward-looking statements made on this call represent our views only as of today and should not be relied upon as representing our views as of any subsequent dates. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements. With that, I'll turn the call over to David.
Thank you, Dave, and good morning, everyone. Thank you for joining. So we're excited to announce positive results from our phase II bivamelagon trial in hypothalamic obesity. As we entered 2025, Rhythm had two major outstanding questions. One, would setmelanotide read out positively in the phase III HO trial? And maybe more specifically, how positively? And two, would one of the two next-generation products achieve proof of concept in hypothalamic obesity? We now have a strong yes for both of those. Today, I'll walk you through the top-line results with a goal of providing as much color as possible to help interpret a relatively small data set. And second, to show as accurately as we can the apples-to-apples comparison with prior setmelanotide data in HO. On slide three, I list the headline takeaways.
B ivamelagon achieved BMI reductions comparable to the 12 and 16-week reductions seen in the similar 12 and older patient population in our phase II and phase III studies of setmelanotide. Setmelanotide, sorry, safety and tolerability were consistent with what we see with MC4R agonism generally, and importantly, we had minimal reports of hyperpigmentation, which I will describe in detail. 27 patients completed the 14-week double-blind portion, and 26 of 28 patients entered the open-label extension portion. Based on these results, we will request the end-of-phase II meeting with the FDA and initiate planning for phase III studies. Moving on to slide 4, I don't think we can have an analyst call without again showing this cartoon of the biology. It's great when something works, but ultimate success is when something works for clear, understandable reasons. The melanocortin biology has been extensively researched preclinically, and now with the advent of specific MC4R agonists, we are validating those findings clinically.
Replacement of alpha-MSH in deficiency states with functional analogs such as setmelanotide and bivamelagon provide a satiety signal with a reduction in hyperphagia and an increase in resting energy expenditure. While the latter is harder to measure clinically, the preclinical data on this mechanism is overwhelming, and the net effect of a satiety signal and an increase in resting energy expenditure results in weight loss or BMI decrease. It's also increasingly clear, as listed on slide five, the mechanism leading to impaired signaling is not so important. As we see patients with genetically impaired signaling or injury to the hypothalamus from a variety of insults, all resulting in decreased alpha-MSH and the potential to respond to an MC4R agonist. As we have noted many times, the simplest analogy here is this is hormonal replacement therapy with a functional analog of the hormone. On slide six, we remind you that these multiple routes to the impaired signaling translate into significant market opportunities globally, with acquired HO being the most immediate and significant of these.
Our estimated prevalence for BBS in the U.S. is upwards of 5,000, with similar numbers in Europe. For HO, we estimate up to 10,000 patients in the U.S., similar numbers in Europe, and 5,000-8,000 patients in Japan. We don't speak as much about the EMANATE trial, which is running, with readouts in the first half of 2026 targeting meaningful populations as well. Very importantly, as we have highlighted, our setmelanotide composition of matter patents extend to 2032, but the formulation patents, which we believe are quite important, extend protection to 2034. Now, with positive bivamelagon data in our first two next-generation programs, we can expect patent protection to be on 2040. Now, the trial results. Slide seven shows the trial design, which was a double-blind randomized controlled trial with four cohorts, placebo and the three doses, 200, 400, and 600 milligrams. Patients were treated for 14 weeks, at which point they could roll into an open-label extension.
The trial remained blinded at that point, so all patients needed to retitrate, and if they were in the 400 or 600 milligram cohorts, they needed to drop back to the 200 milligram, increasing weekly thereafter. All patients in the open-label extension are being dose-escalated to 600 milligrams as tolerated. And I remind you, the trial enrolled patients 12 years of age and older. Slide eight and nine show the patient demographics. Patients suffered with significant obesity with a mean BMI of almost 39. About half the patients were female. 80% of the patients had craniopharyngioma as a cause of their HO. The mean age was 25, and patients on average were seven years out from their insult. Slide nine shows more detailed demographics. The majority of the patients were white, but there were three patients who were Black or African-American and three patients of Asian descent, and four patients of Latino descent. Historically, there has been interest as to the extent of damage to the hypothalamus. As with our other trials, we had patients with both unilateral, arguably less damage, and bilateral involvement in the hypothalamus as per imaging.
On slide 10, as noted, 28 patients enrolled, 27 completed. One patient in the 400 milligram cohort only took medication at the 200 milligram dose as they were dose-escalating for four days before discontinuing due to an SAE, serious adverse event, of lower intestinal bleeding. No specific source was identified. This was judged as possibly related given the absence of an ability to identify a cause. One patient finished the trial but elected not to enter the open-label extension because of ongoing nausea and vomiting related to an episode of adrenal insufficiency that was happening concurrently. They were not taking their steroid dose as prescribed so at present, 26 patients remain in the open-label extension. Slide 11 shows the mean values for each cohort for all 28 patients, including the patient in the 400 milligram cohort who only took four doses of drug. Of note, number one, the placebo group gained weight. There was no placebo effect. Two, there is clear dose-dependent difference, which is what we want to see in clinical development, indicating we are in the right therapeutic dose range, which is critical as we look forward to designing our phase III.
And three, the 400 and 600 milligram groups did quite well with slightly better outcome for the 600 milligram cohort, with a 9.3% reduction in the 600 milligram arm as compared to 7.7% in the 400 milligram arm. On slide 12 is the waterfall plot analogous to what we presented for the phase II data with setmelanotide. First, you can see the placebo patients pretty uniformly gained weight. There was a clear signal in the 200 milligram cohort with one patient decreasing their BMI by 8%. Now, if we concentrate on the 400 and 600 milligram cohorts, I'll provide a little more color. In the 400 milligram cohort, moving right to left, the patient who lost 1.4% is the patient who only took four doses at the 200 milligram dose level before discontinuing due to the SAE of rectal bleeding. That patient has been removed from one of the next analyses I will show you. The patient who lost 4.2% is a 12-year-old female who had ongoing nausea and more specifically challenges swallowing the pills, which led to her gagging, and I'll talk a little bit about this challenge with pills later in this presentation. Her spot trough PK values dropped meaningfully from week six to the week 14 spot check.
We were checking them at their two-week visit, their six-week visit, and their 14-week, so her 14-week spot had dropped significantly. Her maximal BMI change was minus 7.3% at week 10, and she started to regain since that point. The patient's mother works and is not able to regularly monitor the pill intake. So although we lack firm confirmation, we do believe compliance is an issue here. Moving to the 600 milligram cohort, and again, moving right to left, the patient who gained 0.4% is a 14-year-old male who had some nausea and vomiting and diarrhea, which resolved. This patient increased her BMI initially from week zero to week two and then began to lose to a nadir at week six. This corresponded with their peak spot PK trough level at week six. Unfortunately, we do not have a PK trough measurement value at week 14. This patient reported no change in their hunger scores over the course of the trial. The family has been consulted and have confirmed that the patient has been taking their medication. We remain uncertain as to the true level of compliance here, but if they were compliant, then this patient might represent a true non-responder.
The next patient who lost 3.5% had three episodes of diarrhea. In two of the cases, the drug was temporarily discontinued. The PK trough values at week two and six were in range, and in range meaning 500 to 900 nanograms per ml, but which is similar to the values in other patients who had good responses, but the value at week 14 was 13 nanograms per ml, near the limit of detection, and the patient acknowledged being off treatment for a period of days multiple times during the trial. Of note, the patient did have a striking four-point reduction in hunger scores and on DEXA scan at the end of the trial, and the DEXA data has not been cleaned and fully analyzed. We don't have that for you today. But in this patient, their fat mass showed a 10% decrease with only a 1.4% decrease in lean mass, suggesting although the patient was not fully compliant, they were having a clear response to the drug. Importantly, the response in the remaining patients was strong, ranging from -7.8% to -16.4%.
Slide 13 shows you that 70%-75% of patients cleared 5% in BMI and 14%-37% of patients reduced by 10% or more in the 400 and 600 milligram groups, respectively. Slide 14 shows the comparative data that is central focus coming into this data release, and this is our best attempt at an apples-to-apples comparison with the earlier setmelanotide data sets. For both the phase II and phase III studies, we took the patient population 12 years and above and show you the 12-week and 16-week values. We did not have a 14-week data point in these studies. No patients were on GLP-1s in the bivamelagon study, so we removed the patients who were on concurrent GLP-1s in the phase III trial. Beginning left to right, you can see the phase II results with a mean 10.7% and 11.2% decrease in BMI at 12 and 16-week time points. Similarly, the phase III cohorts showed a 9.5% and 10.2% decrease in BMI at the 12- and 16-week time points. Of note, placebo group in the phase III had increased their BMI by 0.6% and 1.5%. Combining the phase II and phase III patients yielded a mean decrease in BMI of 9.7% and 10.5% at the 12 and 16 weeks.
On slide 15, the first analysis of the bivamelagon patients on the left shows the mean for all patients in the 400 and 600 milligram cohort at 14 weeks with a 600 milligram at 14 weeks, with a decrease of 7.7% in the 400 milligram cohort and 9.3% in the 600 milligram cohort. The placebo group increased their BMI by 2.2%. The last two bars correct for the two patients for whom we have documented evidence they failed to take the drug as prescribed. The first bar shows the 400 milligram mean values, removing the one patient who only took four doses of the drug, and that now yields a value of minus 8.8% for the remaining six patients. The last bar shows the mean value for the 600 milligram cohort, removing the one patient who lost 3.5% at week 14 but had documented incomplete compliance with a PK trough level at week 14, which was near the limit of detection, as I said. The mean value for the remaining seven patients in the 600 milligram cohort with the one patient removed is 10.1%.
Slide 16 shows the setmelanotide and bivamelagon side by side with both the all-patient mean analysis and then the final analysis removing one patient each from the 400 and 600 milligram cohorts. Each of these comparisons support the conclusion we have highly similar results at the 14-week time point for both 400 and 600 milligram cohorts as compared to a similar group of setmelanotide patients. Slide 17 shows the statistically significant and meaningful reduction in daily worst hunger scores at 14 weeks. Again, the two to three-point reduction on an 11-point scale is very similar to what has been observed in setmelanotide studies. These patients had baseline values of around seven, which is also highly similar to what we saw in other patients with hypothalamic obesity. Slide 18 shows the safety profile of the drug. We had the one serious adverse event of rectal bleeding, which, as I indicated, was judged possibly related as we were unable to identify a cause. Overall, the safety profile was consistent with what we see with setmelanotide with regard to the nausea and vomiting.
Diarrhea, which has been seen at low frequencies with setmelanotide, was observed at a slightly higher frequency in this trial than was seen in the setmelanotide phase III HO trial, where an approximate 20% incidence was seen in both placebo and treated groups. Although there are MC4 receptors in the gut, mechanistically, it is not clear why that should cause diarrhea. The pill has a high concentration of lactose as an excipient, which will not be present in the next generation pill, but the extent to which that contributes is also unclear at this point. However, what we do know is all cases were mild, except one case judged as moderate. No patient discontinued because of the diarrhea. The episodes were self-limited, with only five patients having more than two reported events, which included one of the placebo patients. Only three patients required a temporary hold on their medication during the trial. And of note, three patients who did have events during the trial had entered with a history of chronic diarrhea. Importantly, we saw no increase in liver function tests in the trial. And then moving to the area of high interest, the question of hyperpigmentation.
Four patients noted an increase in pigmentation, which in all cases was localized and not the uniform darkening we see with setmelanotide. Specifically, the reported events included darkening of pre-existing nevi, darkening of the back of the hands and neck, sun-exposed area, darkening of post-inflammatory skin changes, and in one patient, focal darkening of non-sun-exposed areas, and that patient included the side of the tongue, the right flank, for reasons that aren't totally clear. These were reported in one patient at the 200 milligram dose, two patients at the 400 milligram dose, one placebo patient, and there were no reports in the 600 milligram cohort. Moving on to slide 19, you see a picture of the pill, which is the size of a large multivitamin with somewhat sharp edges. Each patient in this blinded trial needed to take three pills, 200 milligrams of the active ingredient per pill. As you can see, our manufacturing team has done a lot of work where we now have 600 milligrams in one pill, so 90% full drug load as compared to the 26% of what's currently being used in the trial.
Without the same excipients and a slightly smaller rounded pill, the 400 and 200 milligram future pills will be proportionally smaller. We are also well advanced in developing a chewable tablet and a liquid formulation to allow us to treat the younger patients whom we expect will be part of our phase III effort so in summary, what we can conclude at this point, we got a good drug. We appear to be in the appropriate therapeutic range with clear evidence of a dose response and similar efficacy to setmelanotide at comparable time points. The safety profile is consistent with what is seen with MC4R agonism, with a slightly higher rate of diarrhea, perhaps a reflection of the oral route of administration. The contribution of excipients, lactose in this case, is unknown at this time. Minimal evidence of hyperpigmentation was observed, supporting the fact that the drug should represent a significant improvement over setmelanotide in this regard for those patients where this is a concern. We are still relatively early in drug development and learning how we can improve the tolerability of the drug.
First, the pills are large, and the teenage patients clearly had more difficulty swallowing the large pills, which undoubtedly contributed to some of the compliance challenges. Second, a simple adjustment of having patients take their pills with food. They were instructed not to, as a prior food study using a high-fat meal showed a modest decrease in bioavailability. However, for the few patients who started taking their pills with a small amount of non-fat food, tolerability significantly improved. In the open label extension, we are working to make these adjustments. Finally, arguably, patients treated with setmelanotide on the days they choose to take their medicine will get the full dose. Whereas in this trial, any patient who is struggling with pill tolerability might not take all three pills as prescribed, which is harder for us as the trial sponsor to measure. In short, we are optimistic that results will only further improve with some of these modifications. Next steps are outlined in slide 20. We will present the 14-week double-blind data you have just seen at ENDO next week, and we'll be providing an update on the open label extension later in the year.
We will align with regulatory agencies through an end-of-phase II meeting with the FDA and request for scientific advice from the CHMP of the EMA with a goal of initiating the phase III study in HO in the first half of 2026. At this point, I know what we might hope for in terms of the size and design of a phase III study, but it is extremely difficult to predict what the agencies will require. Finally, as a reminder, we have a lot going on. Initiation of our sub-study in congenital HO, the phase II study of the weekly injectable 718 in HO, the open label Prader-Willi study, completion of the Japanese cohort in the phase III HO study to prepare for filing in Japan, and the FDA and EMA filings for setmelanotide in HO, which all remain on track. We remain well-financed with cash into 2027. With that, we'll now open the call for questions.
Thank you. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Our first question comes from the line of Derek Archila with Wells Fargo. Your line is now open. Derek, your line is open. Please check your mute button.
Yep. Good morning. Thanks for taking the questions and congrats on the data. So just two questions from us. Can maybe first just give us a sense of the overall patient drug levels in the trial and whether you think maybe bivamelagon was leaving some efficacy on the table given the pill burden and maybe some of the non-compliance. And then just second question, in terms of what you're going to present at ENDO, I guess there's going to be anything incremental from what we saw today that you'll present at the meeting. Thanks.
Yeah. So I'll take the poster first. So no, on the poster, I mean, we basically are presenting on what you'll see there. So we took some of the surprise out of that. With regard to drug levels, I think so there's a fair range, as you know, on PK levels. And the trough levels I was describing, these are done when patients come in for their visit. They're instructed not to have taken their medication before the level is drawn. They're imperfect for all the reasons you might imagine, but they give you a pretty good sense of whether patients are taking the drug or not and what might be the range. So what we saw was that between the 400- and 600-milligram dosing cohorts, there was a moderate amount of overlap in terms of their PK values, and I think that's reflected in some overlap in the level of amount of efficacy that we're seeing between the two cohorts. You had a two-part question there. Are we leaving efficacy on the table? I don't think we're leaving efficacy on the table in those patients, certainly at the 600, maybe at some of the 400 patients who are taking their drug as prescribed.
Are we leaving efficacy on the table because patients were not as compliant as I think they will be in the future? And that's what I was trying to highlight at the end. I think there's very specific things we can do. And I'll remind you, when we did the setmelanotide trial in HO, we were six years into development, and we had worked out all of many of the kinks. We'd learned how to use it. You remember we started dosing very low, and then in the BBS trial, we actually started dosing at a more mid-range and force escalated, and that tolerability wasn't so great, and so we adjusted. And so by the time we got to the setmelanotide HO trial, we had really worked out a lot of the issues with tolerability around this drug. There's still the MC4R agonism side effects, but we are much better there. So given where we are in development, first trial ever in patients, and the feedback we're getting and the adjustments that are already being made, I mean, I'm very optimistic to the latter half of your question that, yes, we left efficacy on the table here as a function of tolerability, but all of that is addressable, or much of it may be addressable.
Very helpful. And maybe one follow-up. Just in the trial, can you just discuss maybe some of the different HO etiologies that may have been in the trial, and was the efficacy across maybe those etiologies more or less consistent with bivamelagon?
Yeah. I mean, with a caveat, so 80% of these were craniopharyngiomas, which across all of the experience so far, it's been disproportionately, as you know, craniopharyngiomas. And in a 28-patient trial, I couldn't tell you that the others, but there was a difference in response. But there's no evidence. If you put all the data for MC4 agonism together, it doesn't matter what the cause is. It's just, do you have impaired signaling? And if you do, you'll respond, or you should respond.
Got it. Thanks so much, and congrats on the data.
Thank you. Our next question comes from the line of Whitney Ijem with Canaccord Genuity. Your line is now open.
Hey, good morning, guys. Congrats on the data. Excuse me. Just wanted to, I guess, follow up on the line of discussion from the last question, particularly around the titration timing. And apologies if I missed it in some of the intro comments, but was the titration up to the target dose in each cohort fixed? Or as we think about kind of time in range, was there variability around that across cohorts based on that titration, and might that be relevant or not?
Yeah. It's definitely relevant. It's a good question. I don't have the specific details to speak to exactly how much time patients spent at each dose level. We have that, or we'll have it. I don't have it here. But they were not force titrated. The recommendation is patients increased weekly, 200, 400, 600, as tolerated, and there were at least three patients who required a decrease in their dose before increasing again, so we adopted a very similar strategy to what we did with setmelanotide, which is to allow people to dose escalate as tolerated. But again, remembering this is a 16-week relatively short study of which at least three weeks are spent trying to get to your therapeutic dose if you're at the 600, and not unlikely that you may have spent longer getting to 600.
Got it. That's very helpful. Okay. And then in terms of next steps and understanding your commentary that you have to see what the regulators say first, how are you thinking about, I guess, the size of this study in particular? And can you remind us some of the pushes and pulls on the size of the setmelanotide phase III study? As I recall, there was a safety database question that kind of made that patient number higher. So I guess you'd expect that same dynamic to play out here, or how are you thinking about that?
Yeah. I think you answered the question. So yes, we went in setmelanotide asking for a smaller study given the efficacy that we had seen, and if you remember, we were like 99% powered based on what we finally agreed to, which was driven by the safety need. I hope springs eternal. We'll go in and propose a shorter double-blind period. The double-blind period is really tough, particularly when you have a mechanism you know works, and it's a bad problem, so I hope that now the regulators have high confidence and understanding in the efficacy of this mechanism, that putting patients through a long double-blind is maybe not optimal, so what am I hoping for? I'm hoping for a six-month double-blind period.
I don't think we'll get away from my full one year of follow-up, certainly from the safety standpoint, not ironically, but understandably. Part of the reason you need a control group, placebo group, often to determine or evaluate efficacy, but you also need it to evaluate safety. And with this drug, which is a new chemical entity and relatively small numbers of patients treated to date, I think we'll be forced probably to a similar size trial. So my hope is less. My expectation is it'll be similar.
Great. Super helpful. Thanks again, and congrats again.
Thank you.
Our next question comes from the line of Tazeen Ahmad with Bank of America. Your line is now open.
Hey, good morning, David. Thanks for taking my questions. Can you just give us a little bit more color on the localized hyperpigmentation? Do you have a sense of why that's occurring? Does the type of hyperpigmentation differ from the type that you've seen for setmelanotide in terms of the darkness itself, and how long it takes to resolve, let's say, after a patient might discontinue? And then can you just talk about the doses that you plan on taking forward for phase III? Do you plan on including the 200 mg? There was clearly dose response, but how do you offset thinking about needing to titrate to deal with the nausea issue versus needing to max out efficacy? Thanks.
All right. Tazeen, let me see if I get all of this. So skin hyperpigmentation, the more detail. So this is very. So a, I haven't seen any pictures. I mean, we didn't collect pictures during the trial, so I'm just speaking based on reported AEs, which is difficult, and some color talking directly to investigators who have looked at the lesions. So the most consistent among the small number of reports is darkening of pre-existing melanocytic nevi. So why might that be? Higher concentration of melanocytes at this site. If you were likely to see some effect of or be able to pick up some effect of MC1R agonism, you might see it in a place of an increased concentration of melanocytes. Sun-exposed areas, MC1R agonism, melanocytes releasing melanin as part of our protection when we are exposed to the sun. And so chronic exposure there, higher concentrations of melanocytes in those areas, that might link the two. The reports in this one patient who had a couple of areas that were not in sun-exposed, no explanation for that. And then one post-inflammatory changes in the skin. I mean, when we injure ourselves, you get scarring.
That area of the skin can often be darker than the adjacent areas of the skin, and so why is that? Maybe more melanocytes, so again, maybe there's a unifying theme here that says we do have a low level of MC4R agonism, and that's where it's manifesting, but as I said, the others I can't explain so well, and of the four patients, one was a placebo patient, so we are also in a trial where all of the investigators and patients were on notice that they should be looking for this, and the patient with the back of the neck that was picked up by their hairdresser who cuts their hair, and I felt that they looked a little bit different. So I don't know if there's a little observer bias on top of this, but what we are confident in based on this is it's radically different, like I said, the other part of your question, from what we saw in setmelanotide. With setmelanotide, you see uniform darkening of the skin. It happens over a period of two to three months. By the time you get out three months, it plateaus. And then if you go off setmelanotide, it resolves just as the way darkening when we're out in the sun, and then we don't have sun exposure. And over a period of a few weeks, that tends to go away.
So I don't have any data for that in this trial because we don't have patients who come off and or fall in one of these groups to monitor one of those lesions specifically, but I would expect it would be a similar effect. Did I get all the questions? Oh, nausea, dosing. Sorry. On your dosing question, so I expect what this trial I mean, we're thrilled for it because one is, I mean, clearly demonstrates the drug works, and we're getting the similar efficacy. But most equally importantly, I think it's told us that we're in range. And so the dosing paradigm that I would expect us to use for the phase III trial is we'll start at 200, and we'll dose escalate to 600. We'll do it exactly the way we guided patients starting at one milligram and dose escalating to three milligrams with setmelanotide, as tolerated, with the ability to down titrate and then increase again as tolerated.
Some patients may end up at a lower level, A, because they're getting the response that they desire, or B, they just cannot tolerate for whatever reason the higher dose. And I remind everybody, it's always of the many things that amaze me about this clinical development program is just how incredibly complex and in many cases sick these patients are. So the fact that, A, they're highly motivated to take this drug because it makes such a difference, or this mechanism of action certainly, take the drug, is instructive. And the fact that we get such uniform results given the complexity of their medical problems. There's high heterogeneity patient to patient in terms of other stuff that's going on.
Okay. And maybe just a follow-up, David, on the hyperpigmentation. Does the level of sun exposure have a factor here? I don't know if these patients might have been on trial during the summer season and might have affected anything.
No, I don't think so. And again, I'll just go back. It's not every sun-exposed area. I mean, what's being described is incredibly focal. The thing I'm really hanging on, which makes me feel this is real, is the consistent, meaning of the four patients. Remember, one of them was placebo, but certainly the darkening of the nevi. So I think that as a readout that you are getting some MC4R agonism is there. I don't know what to do with it, to be honest with you, the back of the neck and the hairdresser is part of the story. I mean, I've given you a hypothesis. I think that's reasonable and that that may in fact be true, but I have no more color beyond what I've told you, so.
Okay. Thanks.
Thanks.
Our next question comes from the line of Phil Nadeau with TD Cowen. Your line is now open.
Hi. Good morning. This is Phil Nadeau with TD Cowen. Congratulations on the data. A couple of questions around the side effects from us. On the nausea, can you talk a little bit more about the quality and duration of the nausea? How long lasting was it? And is there any difference between the nausea experienced here and either the severity or duration compared to what's experienced with setmelanotide? And then, on the diarrhea, I think you mentioned that there were four drug patients who had more than a few episodes. Was the likelihood of having longer duration of diarrhea also correlated with dose or was it correlated with dose? Then, last question in terms of the placebo, I think you've called out lactose as perhaps adding to some of the AE tolerability issues. Did the placebo pill also have a similar amount of lactose in it? Thanks.
I think the last. Yeah, thanks. I think last one first. Yes, the placebo pill had the same amount of lactose in it. So the fact that we saw diarrhea in a placebo patient, certainly that could be a factor. So four episodes of diarrhea. Sorry, I lost the first part of your question there.
So I guess first one was on nausea. Any difference in the severity or duration compared to what you've seen with setmelanotide?
Yeah. No, sorry about that. So no, I would say the nausea with one caveat, which I'll tell you in a minute. The nausea is highly similar to what we see with setmelanotide, and that's where I think very consistent with this MC4 agonism on target mechanism, if you will, occurred early, pretty variable, meaning some patients tolerated it much better than others, but everybody, as a rule, tolerated over time. Now, the caveat, and time meaning a matter, and this is only a 16-week trial, but over the period of four plus or minus weeks kind of thing. The caveat being that the size of these pills and the patients who had the most trouble in this trial tolerating the medicine were the teenagers. Specifically, the teenagers, we had like four patients between sort of 12 and 14. Those are the ones who described choking on the pill, gagging on the pill, just taking it. So I think that confounds a little bit of the reporting on the nausea piece. Then the second, in talking to investigators, there's another confounder here, which is they said for some of them, it wasn't like the setmelanotide nausea per se, but what they were hearing was more of a gastritis, so stomach irritant.
That's where going back to this issue of you're taking these three large pills on an empty stomach. For patients, and it was a relatively small number, but I think that experience is informing us, and I think it's true, that with a little bit of food, tolerability dramatically increased. So I think as we go forward, we're going to tease this out a lot further. But no, it was pretty much spread across all three groups. I'll tell you exactly. 16 patients had reported nausea, three in the placebo, six in the 200, four in the 400, and three in the 600. So it wasn't that it's just the higher you go, the worse it gets kind of thing. It kind of, I think, was more patient-specific and maybe colored, actually highly likely colored by the fact that not all of the nausea was the same. It may have been different in different patients, as I described.
Got it. And then in terms of the diarrhea, was it more likely to be longer lasting at higher doses, or was the chances that?
No. So yeah, no, thanks. So I'll tell you that. So, on the diarrhea of the cases, so there was one in the 200, two in the 400, and sorry. Actually, I just confused my numbers here. But no, no, sorry. Now I got it. It was spread evenly across the three. Sorry. There was three in the top groups at 600, four in the 400 main group, and a smaller number in the 200 and some in the placebo. But it was spread pretty much evenly across the groups.
Got it. Thanks for taking our questions, and congratulations again on the data.
Our next question comes from the line of Dennis Ding with Jefferies. Your line is now open.
Hi. Good morning. Thanks for taking our questions, and congrats on the data. I had a big picture lifecycle management question. I was wondering how you envision positioning some of these second-gen drugs, whether it's the oral or the weekly or both, once they're approved, and how would you incentivize switching from setmelanotide before generics launch, and how does that kind of strategy change after generic launches? And then my second question is just around your prior comments on non-compliance with the oral. Presumably, the weekly sub-Q could help with some of that. So talk about your expectations for that weekly update. And is it unreasonable to assume efficacy could look better just on better compliance and perhaps less daily PK variability? Thank you.
Yeah. Thanks, Dennis. Let me take the last part first. Does this read through in any way to 718? I think only in the sense that it confirms MC4 agonism works. So we've had high confidence all along, and as you and others have we've discussed, if we knew nothing and you said, which is more likely? W e said, well, 718 seems more likely because it's a peptide, and it's sort of recapitulating what we've already done with setmelanotide. And so that would seem more likely, the small molecule having more unknowns. Now we have the results for the small molecule. And I think what it's saying to me is that, one, as I said, the small molecule is working as a good MC4 agonist. The fact that the results are so similar to what we saw with setmelanotide at comparable time points suggests that we're getting more or less the full efficacy of MC4 agonism from this drug at these time points. Can we do better with this drug? I am absolutely convinced because back to my earlier comment, there are things we can modify here, and we will modify that will translate to greater tolerability and greater compliance.
The bigger picture question you said, in general, will we get better compliance with a weekly than you do with a daily oral? I would say that's probably true. Will everybody prefer a weekly over a daily oral just because of that? I don't think that's true. I think there's many patients who want nothing to do with needles, who will be very happy with an oral medication. There'll be maybe parents who don't want to be injecting their kids and the like. So I think what we're aiming for with this portfolio strategy is a portfolio of products, two in this case, which basically cover the needs of all patients. As a company, we're not going to be pushing people one way or the other. Hopefully, it'll be very much a patient-driven decision. Now, why would they switch? At the end of the day, both of these, simply from a tolerability standpoint, a daily oral and a weekly injectable as opposed to a daily injectable should be preferred.
And to the extent, and I'm quite confident based on the reports we have now, we've dramatically decreased the hyperpigmentation piece of this. I think 718 is likely, based on our preclinical data and the like, to be even less likely to have hyperpigmentation associated. So the switch will happen because patients see this as preferred treatments. I don't think we'll need to convince people to do that. But we have the advantage, again, as a company, in a rare disease world, we're very close to this patient community. We'll be able to interact individually with patients who sign up and consent to talk to us. And we're available to help them think this through as needed.
Thanks. And what about after generic is launched? And maybe talk a little bit about your expectations around payer reimbursement in that sort of landscape.
Yeah. Again, you and I have talked about this. When a generic is launched into a rare disease space, and my experience, which I guess has grown over the years, they almost never, never compete on price. It's rare diseases. If you cut the price, you can't make it up on volume. The incumbent, the first mover, has an enormous advantage here against rare diseases, relationships that are built, patient support programs that are out there. So if and when a competitor comes in, they'll tend to price similarly and then just go out and compete for share. And in that setting, it will do fine.
Sounds good. Thank you.
Thank you.
Our next question comes from the line of Mike Ulz with Morgan Stanley. Your line is now open.
Good morning. Thanks for taking the question, and congrats on the data as well. Maybe just could you talk a little bit about timing of the new formulation tablet? What are the next steps there, and when will that be available, and could that be rolled into the pivotal? Thanks.
Yeah. That's fine. Yeah. Important question. So when I said that our goal is to start the phase III trial in the first half of 2026, it's Joe Shulman, our head of Tech Ops. As we said many times, our goal is to keep him off the critical path there. We will not start the phase III trial without that. And I think we're in really good shape for having that ready and ready to go. He's already got the pill. I mean, now we're, I'd say the next steps are finalizing the development of the chewable tablet. We don't need the liquid, to be honest, going down. We actually did that first. We've completed taste testing on the liquid and the like. And so we're really quite advanced on the liquid. But I think going down to age four and above, it's probably just a chewable tablet, plus the pills will allow us to cover that population of the study population we're studying and get underway in the first half of 2026.
Great. Thank you. And congrats again. Thanks.
Our next question comes from the line of Seamus Fernandez with Guggenheim. Your line is now open.
Oh, great. Thanks for the question. So I wanted to just get a sense on the hyperpigmentation, what you're seeing in terms of it seems like you're not really seeing much at all, that those are kind of case reports that are coming in infrequently and more sort of spot-related. But as it relates to setmelanotide through 12 and 16 weeks, just wondering where the hyperpigmentation kind of tends to peak. Is that something that intensifies over time with further exposure? And was there any evidence of a time-delimited increase or any hyperpigmentation events that were time-delimited as you went from, let's say, eight weeks to 16 weeks? And how does that profile compare to the profile for setmelanotide? And then just my second question, can you just remind us with 718, your weekly subcutaneous injectable, what the sort of selectivity profile relative to MC4 over MC1R is, and if you would anticipate potentially having an even better profile with almost no hyperpigmentation between bivamelagon and 718? Thanks so much.
Yeah. Thanks, Seamus. So the profile for setmelanotide, it's over the first three months. It obviously varies. The darker you are, the darker you get. But it develops over the first three months as a rule. It tends to plateau once you get out three months. There's clearly a dose-dependent effect. I mean, if you're on very, very low doses, you may have less evidence of hyperpigmentation than if you're at the 3-mg dose with setmelanotide. The same might be true here, although we don't have any indication in the small number of patients that it was dose-dependent. Your question was, is there a timing? No, the four events were a little bit spaced out. I would say, yes, they came to awareness more sort of mid-later part of the trial, so consistent with what we'd expect to see with setmelanotide. I don't think that's different. Again, I do question back to the placebo patient who reported and the like, whether there may be a little bit of observer bias. If I was just to take the increase in melanocytic nevi pigmentation as the best marker, those tend to be sort of mid to late part of this double-blind period of the trial.
In terms of selectivity preclinically and what we might see with 718, so the bivamelagon is five times more selective, more or less, plus-minus for the MC4 receptor over the MC1 receptor. We've now run this data internally, and we've got much better clarity. So it's a little less specific than we had thought originally when we licensed the compound. But 718, it's like 1,000 times more selective. So the probability that we see something there to the extent what's incredibly reassuring is, A, we're not seeing much here, hardly anything. And then if 718 is truly, as we believe it will be, that much more specific for MC4, then the risk we see something there is even lower.
Just as a quick follow-up to that, those relative comparisons that changed from the first assay to this assay for bivamelagon, is that 1,000-time differential sort of similar, or would you anticipate just sort of a directional change? I know 1,000 versus 5, if that is the case, is something that we can be very comfortable with in most directions. But I just wanted to kind of confirm if that was on the same assay.
That is on the same assay.
Excellent. Thanks so much, and congrats on the data.
Thanks.
Our next question comes from the line of Leland Gershell with Oppenheimer. Your line is now open.
Thanks for taking our question and adding our congratulations on the results. Just a question as we talk about dosing between setmelanotide and bivamelagon. If you could remind us, to what extent was setmelanotide dosing weight-based in its phase III HO study versus here you have kind of fixed doses that are titrated? Wondering if, A, that would make it easier potentially for patients who are on the oral, less burdensome in terms of having to titrate as they lose weight. Also wanted to ask if you could see patients once they lose a certain amount of weight on bivamelagon, could they maybe downgrade to a lower dose as a maintenance? And that could also lighten the effects on the skin hyperpigmentation. Thank you.
Yeah. So how does the dosing compare between bivamelagon and SET? So we don't dose on weight. And from early on with setmelanotide, we've never dosed on weight. Now, that's not to say at some extreme point it's not an issue, and we know it's an issue. So for example, let me modify a little bit what I said. When we did the study in the two to six-year-olds, we used lower doses. Now, in that two to six-year-old group, we had a leptin receptor biallelic patient who at a very young age was extremely obese. And this was the patient who had little to no effect or minimal effect from the drug, and we lost him from the trial. And I know we were underdosing that patient based on weight. They just didn't get to a therapeutic level. They were much more like an older individual despite being less than six. So there's definitely, at some point, weight becomes an issue, but over a wide range, it's not.
So we just have a standard dosing paradigm, one to three milligrams. It's the same for the six-year-olds, the same for the 66-year-old. B ivamelagon, I expect, again, mechanistically to be similar. So I don't expect with that caveat that at the extremes, dose may be an issue. But I think what this data set, despite its small size, is telling us, we're good. We're in a range here where we should be able to count on seeing the efficacy we'd expect to see and not needing to modify, again, because of weight per se. What was your last thing on the hyperpigmentation? No.
Oh, just wondering if over time, you could see patients losing kind of weight and then moving to a lower maintenance dose with maybe better maintenance.
No, no, no. That's a good question. No, I think about it again as it's hormonal replacement. It's like if you were on thyroid and you get your thyroid fixed, you monitor the levels. Unfortunately, we can't monitor alpha-MSH levels. But patients will get what they're needing to saturate that receptor and get the benefits on the satiety signal and the energy expenditure and restore, hopefully, their physiology relatively normal. But then you'll just live there. It's like thyroid again. You don't get in range and start feeling well and stop your thyroid or decrease your thyroid dose. You just keep it.
Got it. And then just one follow-up, if I may. We just noticed in the slides, we have four patients on bivamelagon with skin pigmentation and none in either 600 or placebo. In the press release, you also mentioned four patients, but it also has that those included one placebo patient in that sentence. If you could comment on that discrepancy. Thank you.
Okay. Shoot. Discrepancy here. Two at the 200, two at the 400. Oh, so we did have one in placebo. Yeah. Okay. Leland, I'm not sure. I'm going to go back and check that. Yeah. I'll go back and check that. I can't explain the discrepancy right now, but I think what you can count on, what I know as a fact is there's zero at the 600 milligram, and then the cases were at the 200 to 400. So it wasn't clearly at the higher doses you were going to see this. And I know there was one placebo patient, so we'll clarify.
Got it. Okay. Great. Thanks very much.
Thank you.
Our next question comes from the line of Jon Wolleben with Citizens. Your line is now open.
Hey, thanks for taking the question. And congrats on the data. I wonder if you talk a little bit about the open-label extension. What's the longest follow-up you have today? When do you expect to report data? Do you expect to see continued benefit over time like we saw with setmelanotide? And then any comments on if patients are staying at the lower doses in the open-label extension or if people migrating back up to the 600-milligram dose? Thanks.
Yeah. Thanks. I don't have detail on where they are exactly in terms of their dose escalation, everybody staying in, and so presumably they're tolerating it. I think our experience with the double-blind phase would say that patients, they may dose down as they're just to get through a period of low tolerability and then be able to dose up. But it seemed to be we managed that through pretty well in the open-label. And sorry, in the double-blind, I'm expecting a similar in the open-label here. In terms of where we are, yeah, we're going to talk about it in the fall. Obviously, given when the trial finished, we're well into everybody now is in the open-label extension rolling forward.
I'll tell you, about half of the patients have reached their 28-week time point. But we'll look forward to reporting that out in the fall. And yes, what do we expect? I expect patients to continue to lose weight. I mean, that's the nature of this thing. And I'll go back to one of my best-case examples, which is in our phase II, the famous 24-year-old patient who started out with a BMI of 52. Their BMI is 24 now, so they had an amazing response. But that happened over four years. They just ground down over a period of four years relatively steadily. And so other patients have plateaued. So it's no guarantee. But in general, we expect patients to continue to lose more weight.
Thank you. Next question. Our next question comes from the line of Faisal Khurshid with Leerink Partners. Your line is now open.
Hey, guys. This is Matt Cowper in the call for Faisal Khurshid. Thanks for taking my questions. So any thoughts on why the AE profile on the whole looks a little better at 600 than 400? And then for hyperpigmentation, thoughts on the reverse dose response there? Is that just incidental? And then for bivamelagon, I know you've inherited the phase II and rare genetic disorders of obesity. But how are you thinking about development and timelines for indications beyond HO now that you've confirmed its MC4R agonism effects? Thanks.
Yeah. So thanks, Matt. For the 600-milligram, sorry, what was the first question in terms of AEs? The hyperpigmentation, there was, I think, oh, sorry, the whole thing is just a matter of small numbers in terms of how this distribution is. We have relatively small numbers in the 600. I don't think there's a difference between 600- and 400-milligram profiles. I think the absence of some of this stuff at 600 just tells you that it's not a clear dose-dependent effect, but it's a little bit more heterogeneous depending on the background state of the patient, perhaps, for some of these, how they're feeling. In the 400 mg, we had a couple of kids who really struggled. They were the kids who had some nausea. They had trouble gagging on their pills. A couple of them had some diarrhea. So some of those events clustered in a smaller number of patients in that group. And then let me know if I answered that question.
And then development beyond HO, how do we think about that? The HO is by far, as we know, the largest opportunity. So of course, we'll develop both the oral and the weekly in that indication. We will look to get one or both of these approved in the other indications that we are approved for today, so specifically the BBS and PWS. How we do that, what's the most efficient way to do that? I think we need to learn a little bit more about the drugs and what we think will be the best strategy there. I think we can commit. We'll take one of them forward into both of those, but I'm not sure at this point we commit to taking them both forward.
Got it. Thanks for taking my questions.
Great. Thank you.
Our next question comes from the line of Paul Matteis with Stifel. Your line is now open.
Hey, this is James. I'm for Paul. Thanks for taking our question. And congrats on the data. Maybe just one last one here. I think a lot of the questions have been asked here, but wondering if there's any more color on the rectal bleeding SAE. And whether you think it's truly drug or mechanism-related or not, any color there would be great. And congrats again. Thanks.
Yeah. Thanks, James. Yeah. No, this is a challenge to AEs. One of the things that helps you in drug development over time are large data sets, right? So when you've treated 1,000, 2,000 patients, more than 2,000 now with setmelanotide, you have a lot more understanding of how to interpret some of these events. This is just early development. So this patient, they had a history of hemorrhoidal bleeding. It doesn't seem like this was that. They did come in, as I indicated, with lower intestinal bleeding. They did not get a colonoscopy. I don't know why, to be honest with you, which is, I think, probably a normal workup for that problem. So no specific site was identified. It resolved. It has not recurred to the best of my knowledge.
The patient is discontinued from the trial after only four doses. They'd only received the 200-milligram. They were dose escalating. They were in the 400-milligram group, but they were dose escalating. So they were only at the 200-milligram dose at the time they came in. So you're left in this case, mechanistically, there's no reason. We haven't seen MC4 agonism leading to lower bleeding of any sort. So there's no real mechanistic reason for why that would happen. I honestly think this is unrelated. The investigator put it down as possibly related, which is what they need to do if they don't have a cause, and could it be? I guess we're early on in development, so you put down possibly. So I don't have more information than that, but what you're hearing is this is not an issue for us.
Makes sense. Thanks so much.
Our next question comes from the line of Joseph Stringer with Needham & Company. Your line is now open.
Hi. Good morning. Thanks for taking our question. Just to follow up on the non-compliance or suspected non-compliance, you mentioned some of the patients had trouble taking the large pills, which if they were in the 600-mg cohort, they had to do that three times per day. So with the new tablet, you have the once-daily 600 mg, but pill size looks very similar looking at slide 19, maybe slightly smaller. So I guess my question is, was the suspected non-compliance mostly due to the fact that the patients had to take three pills per day, or was it simply the size of the pills, or was it maybe a combination of both? And then how confident are you that the new tablet can address the non-compliance issue? Thanks.
Yeah. Thanks, Joseph. So just to be clear, every patient had to take three pills. So if they were in the placebo group, they got three placebo pills. If they were in the 200-milligram group, they got one active and two placebo. So every patient every day was taking three of these large pills. So not fun, as we understand it, for the patients, number one. I think we all tolerate medicines differently. I think the rounding of the edges will make a significant difference. Definitely going down from three to one pill will make a big difference. And then, as I said, the 400- and 200-milligram versions of this new generation will be proportionally smaller. So we have a lot of room to work with. That's my message, number one.
And number two, these other just minor adjustments, taking a pill with a little bit of food, which we can do, of course, with the next generation, also, I think, will have a huge benefit here. So again, I'm quite confident, and yes, sort of level of confidence. I'm quite confident we can do much better on the tolerability. And I'll go back to what I said earlier, right? We're super early. 28 patients into our patient experience here, and we've learned a ton. We're well advanced here in terms of, A, what we've learned, and B, how I think we can address some of the specific issues to get even better outcomes.
Thank you. This concludes the question-and-answer session. I would now like to turn the call back over to David Meeker for closing remarks.
Great. Thanks all for tuning in again. As you've heard, it is another good moment. I think we all internally maybe had some questions about how all this would work out. Until you get the data, you don't know. Now we have it, and we're excited about it. I think there's a lot you're going to be hearing as we go forward. We look forward to our next update. Thank you.
This concludes today's conference call. Thank you for your participation. You may now disconnect.