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

Good day, and thank you for standing by. Welcome to the Rhythm Pharmaceuticals Conference Call on hypothalamic obesity. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to Dave Connolly, Executive Director of Investor Relations and Corporate Communications. Please go ahead.

Thank you, Andrea, and thank you all for joining us this morning. For those of you participating via the conference call, there are accompanying slides that can be accessed and controlled by going to the events section on our Investors page at our website, ir.rhythmtx.com. This morning, we issued a press release with our Phase II data from a trial evaluated setmelanotide in hypothalamic obesity as well as the design for our Phase III trial. The press release, which is now available on our website. Here on Slide 3, I'll remind you that this call contains remarks on 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 report on file with the SEC. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views of any subsequent dates. We specifically disclaim any obligation to update such statements. On the conference call today, with us live from San Diego are listed here on Slide 3. Dr. David Meeker, our Chief Executive Officer, Chair and President; Dr. Christian Roth, a Pediatric Endocrinology Specialist at the Seattle Children's Research Institute at the University of Washington. He is a clinical and research focuses on children with early onset obesity, children with brain tumors and complex endocrine disturbances such as hypothalamic obesity as well as other endocrine disorders. Also Hunter Smith, our Chief Financial Officer, is available for the Q&A portion of our call. With that, I'll turn the call over to Dr. Meeker.

Thank you, Dave, and good morning, everyone. Thank you for joining us as we present the full data set for our 18 patient acquired hypothalamic obesity trial. As you will see, these results are confirmatory of the interim data presented in July. We are also pleased to report that we are granted breakthrough designation, which we announced yesterday and that we have reached agreement with the FDA on the Phase III trial design. So starting on Slide 4. Let's start with an overview of the strategy for building rhythm. You know this well. This is quite simply to execute on the commercial opportunity represented by our approvals and continue our work to study the expanded opportunity in both other genes linked to the pathway and now, of course, in the acquired plum of injury to hypothalamus, which we will discuss today. As you know, IMCIVREE is approved for POMC, LEPR, PCSK1 homozygous deficiencies and for Bardet-Biedl syndrome in both the U.S. and Europe. We very much look forward to updating you next week on our third quarter earnings call and the progress we are making in both the U.S. and Europe. We also continue to progress our development programs designed to expand the patient population eligible for IMCIVREE. Moving to Slide 5. Now let's turn to HO. So this is a population we estimated 5,000 to 10,000 patients in the U.S. and a similar sized population outside the U.S. We're very excited about this opportunity, needless to say, for the reasons highlighted on the right side of the slide. This is a significant unmet medical need, no treatments are approved for use in this population, and nothing has worked consistently. The biology is clear. These patients suffer from injury to the hypothalamus, not a genetically driven impairment. That injury is most often due to tumors usually benign, that are either -- that either injure the hypothalamus through direct extension into the hypothalamus or the injury occurs secondary to the surgery and radiation, which is used to treat the tumor. Unlike our genetically defined populations where genetic testing is required and a significant percent of that population is undiagnosed, this is a population which is largely diagnosed. These patients experienced an abrupt dramatic change in their health with a rapid BMI increase, which is often associated with hyperphagia. Importantly, they remain engaged with the health care system since the injury often involves the pituitary gland and they require one or more hormonal replacements to manage the pituitary insufficiency. The physicians who manage this problem are endocrinologists and pediatric endocrinologists predominantly, and these are exactly the same positions we are actively engaging with the other approved indications for IMCIVREE. So on Slide 6, this is the familiar cartoon of the anatomy. And as you can see, these tumors tend to originate in the space between the pituitary gland on the bottom of the slide and the hypothalamus on the top. The associated injury leads to impairment in the melanocortin pathway as well as other neurons in the hypothalamus with the associated decrease in energy expenditure, hyperphagia and as a consequence, rapid weight gain. So moving to Slide 7. So now let's talk about the results from the trial. We enrolled a highly heterogeneous population. There were 18 patients with 13 of those patients being younger than 18. The starting BMI upon trial enrollment was 38% for all patients. The BMI-Z for patients 6 to younger than 18 was 3.9, which means that their BMI was 3.9 standard deviations from what is considered normal. The majority of the patients had a craniopharyngioma, but we did have 3 patients with a hematoma, and one with an astrocytoma. There are event where hypothalamic damage that caused their [indiscernible] to occur between 6 months and 15 years prior to enrollment. On Slide 8, we show the trial schematic. This is an open-label 16-week trial with those patients less than 16 started on 1 meg and dose escalating to 3 megs, whereas those older than 16 started at 2 and dose escalated to 3. The primary endpoint was the percentage of patients decreasing their BMI by 5% or more at 16 weeks of treatment, which includes the dose escalation period. On Slide 9, we show the top line results. 16 of 18 patients lost 5% or more, and 14 of 18 patients lost 10% or more at some point in the 16-week trial period. The mean BMI decrease for all patients at 16 weeks was 14.5%. Now on Slide 10, the next few slides they are probably the most important slides in the presentation, beginning with this waterfall plot. And I'm going to spend a little bit of time walking you through because there's a lot of bars on this page. So the dark blue bars represent the data we presented in July. The light blue bars are the incremental 7 patients. We are going to focus on the purple box on the right-hand side of the slide, which showed the 5 patients who are not at a 10% or greater BMI decrease at their 16-week end-of-trial visit. The white bar for these patients represent the maximum weight loss during the 16 weeks. The blue bars are their values at 16 weeks. So let's start with the 2 patients on the left side of that purple box. These are the 2 patients we described in July who stopped the drug due to an adverse event before reaching 16 weeks. To remind you, the first patient had a dramatic response to the drug with a 70% decrease at BMI at 4 weeks and was then found to have an increase in liver transaminases, which was confirmed on drug rechallenge. The drug was stopped. And at 8 weeks, she had regained some weight with a BMI of minus 6.9% baseline. The second patient had lost 8.2% at 12 weeks but was unhappy with their skin hyperpigmentation. At our last visit at 16 weeks, she also regained weight with a BMI of minus 6.7. As discussed in July, we felt both of these patients had a clear and significant response to the drug, and we're on track to lose 10% or more at the 16-week point. The third patient in the middle of the box did decrease their BMI by 10% at 12 weeks but was having nausea. Her dose was decreased to 0.5 megs and she regained weight with a BMI increasing to minus 6.7% at 16 weeks. She has now had her dose increased again, and as I will show in the next slide, is losing weight. Finally, we have the 2 patients who did not lose 5% or more weight. The patient on the far right, who regained weight was not compliant and returned the majority of his drug unused. He was discontinued from the trial. The last patient is perhaps the most interesting patient. The patient tolerated the drug well, rapidly dose escalated to the target dose of 3 megs. At the end of the 16 weeks, they had decreased their BMI by 2.7%. There's more to the story as I will show on the next 2 slides. So on Slide 11, this is a spaghetti plot of the 5 patients not reaching 10%. The red line and the blue line are the 2 patients who discontinued during the 16 weeks due to adverse events. The purple line is the woman who regained weight when her dose was decreased to 0.5 megs and is now losing weight again in the long-term extension, where you can see a decrease to minus 9.7. The dotted line is the patient who is noncompliant. The black line is a patient who, as you can see, continue to gain weight during the dose escalation period in the beginning of the trial, and at 16 weeks has then decreased their BMI to minus 2.7% from baseline and 4.2% from their peak BMI value. You can see that the patient has continued to slowly decrease their BMI and importantly, as I will show you on the next slide, is no longer increasing the BMI. So on Slide 12, this is the patient's growth chart. This is a patient of Dr. Roth, and he can provide a little more color on this patient at the end of the study -- at the end of my presentation. But this patient has undergone multiple surgeries at the time of their original diagnosis and had their last surgery performed in 2019, and the belief is it -- it is his last surgery, which precipitated the development of this patient's hypothalamic obesity. So this patient had been diagnosed with a bilateral hypothalamic hematoma. The patient was 11 years old at age of trial initiation. And what is striking is the severe and rapid increase in that patient's BMI, which is now reversed, albeit more slowly and less dramatically than some of the other patients. So I'm now moving to hunger on Slide 13. Hunger scores were measured in patients aged greater than 12. Baseline scores were 6.6 on average and decreased by 2.9 points, a 45% reduction. This is consistent, if not slightly greater than the changes in hunger scores we have seen in other populations. On Slide 14, more data on the hunger. You can see the consistency in the hunger reduction from baseline across all patients for whom we have hunger scores. And again, these decreases for all but 1 patients are measured against their own baseline. And as you can see here, 8 out of the 10 reported a reduction of about 20% or greater. So on Slide 15, before discussing our long-term open label data, let's briefly review the disposition of all 18 patients on Slide 15. 14 of them went on to enroll in the open-label extension, including Dr. Roth patients who did not achieve the primary endpoint. During the 16 weeks, we had 2 discontinuations, 1 for hyperpigmentation and 1 with elevated LFTs. We have the 1 patient who completed the 16 weeks of therapy but decided not to enroll and we have the 1 patient who is noncompliant. So on Slide 16, here's the long-term extension data. And this is obviously a critical question is what happens beyond 16 weeks. And just to remind you, there was no diet and exercise support here either as we run most -- all of our trials to date have been done without that support. And as you can see here, the data from 13 patients who have reached at least their first long-term extension visit, which occurs at 13 weeks following the end of the original trial and the data from 5 patients who reached their second long-term extension visited approximately 25 weeks. The mean BMI decrease was 21.1% and 26.7%, respectively. These results are consistent with the hypothesis that we are correcting underlying biology with secondly -- likely interacting with any remaining MC4 receptors in the hypothalamus and receptors outside the hypothalamus in the brain stem and spinal cord. Results also suggest we are not -- we are seeing not only a reduction in hunger but an increase in energy expenditure, which is difficult to measure, but likely contributing to the decrease in BMI. So in summary, these results give us a lot of confidence going into this Phase III study. So on Slide 17, let's move to the Phase III study. We have met and reached along with the FDA on trial design. And as I indicated at the start, are pleased to have received breakthrough designation. This reflects both the strength of our interim Phase II data and a significant need for a novel therapy syndication. This designation expedites our development for HO and the FDA's review on potentially reducing overall review time to approval by 6 months. So on Slide 18, in Phase III trial, as we expected, will be a double-blind placebo-controlled trial enrolling 120 patients aged 4 and older randomized 2:1 to treatment of placebo. The trial will include an 8-week titration period with 52 weeks of the therapeutic dose. On Slide 19, we have the details on the primary endpoint in key secondaries. The primary compares BMI reduction achieved on setmelanotide compared to placebo at 52 weeks. Of note, with 120 patients at 2:1 randomization ratio, the trial is powered at 99.5% to detect placebo-adjusted difference of 10% and with a 2-sided alpha of 0.05, assuming a common standard deviation of 10%. Key secondary endpoints include the proportion of patients who achieved greater than equal 5% reduction in BMI from baseline in adults greater than 18 or BMI-Z score reduction of greater than equal to 0.2 baseline in pediatrics after approximately 52 weeks on a therapeutic regimen compared with placebo. And lastly, a mean change in the weekly average of the daily most hunger score in patients greater than 12 from baseline for approximately 52 weeks. So with that, we've completed the formal part of the presentation. But before we open it up to questions, I'd like to ask Dr. Roth to make a few comments. So first, Dr. Roth, thank you for joining us this morning, probably helpful, and thanks for your support in the clinical trial. I wonder if you could make a few comments just on why is it so hard to treat these patients with hypothalamic obesity? And how does that contrast -- what differs on patients with general obesity?

Thank you for this question. As you already mentioned, this is an acquired form of obesity, acquired injury to the hypothalamus because of the brain tumor. And this is an abrupt change of body rate regulation because these tissues that are major tissues for the homeostasis. And as homeostasis, they are partially or completely removed and this causes a dramatic change in appetite control. And so typically, in those patients, they tell that they cannot control their appetite and within a very short time after surgery, they gain quickly weight. There's also the problem that they -- the energy expenditure part is affected by this injury. That means that the energy expenditure is very low. So even if they cut down on carry intake, they are typically not able to lose weight because their energy expenditure is on energy savings. So they save energy and do not burn easily energy. Their activity level is very low. And therefore, it's a different entity of obesity and a very difficult to treat entity of obesity. We have used different drugs in the past and I have not seen such a strong response to a drug intervention before.

And then maybe we -- I presented your patient who was the -- a bit of an outlier in terms of overall response here. And I wonder if you had a few additional thoughts on that patient, why they might be different or how you see their response.

He is a very complicated case in that respect that he has not just obesity and history for brain tumor, but he had several surgeries and total number of 4 surgeries. And with repeated surgeries, we know that there is more tissue damage in the hypothalamus. So I believe that it's a very extensive damage of the hypothalamus in a way that you cannot actually see in the MRI scan. It's not just a lesion. It is maybe also some scar tissue because we had laser interventions, so laser surgeries before. And then he has also some other problems. He has cognitive -- significantly cognitive delay and autism also and those patients are typically more difficult to treat because they are more difficult to educate on some weight reduction goals.

Great. So operator, I think now let's open it up for Q&A.

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

Congratulations on the data. They continue to look very impressive. Just a couple of questions from us. First, on the change in hunger score. I'm curious if either the company or the physician could give us some sense of what's considered a clinically meaningful change in hunger score. What improves the quality of life of these patients? And then second, on the pivotal trial, can you speak a bit about the enrollment criteria in the trial? What have you learned from the -- from this first trial as you construct the enrollment criteria? Are any group is going to be excluded to improve the chances of success?

Yes. So maybe I'll make a comment and then Christian, if you could. So on the hunger score, just to how this compares to our other studies. So we saw on the other studies, the genetically impaired forms of injury, if you will, impairment about a 2-point decrease. So this is very consistent with that. And if you remember, one of the things that was striking about the Bardet-Biedl trial was that 2-point decrease when we looked at it and lined it up with the patient narratives, the family narratives, which were -- the narrative themselves were quite descriptive and compelling in terms of how that reduction and hunger has changed, not only the life of the patient, but overall dynamics from the family was quite remarkable. So from that standpoint, the 2-point decrease and we saw almost 3 points here, it was significant. Now how that compares across population remains a question. But Christian, from your standpoint, when you look at the decrease in hunger, how would you characterize the patients' response in your experience.

Yes. Just talking about the narrative, what patients experienced and after the parents talked to us, it was very clear. There was a significant change in eating behavior and also desire to eat and to stay away from food for a longer time for several hours. So that was in some of the patients really changing their lives. They're back to normal and are not obsessed with food all the time.

So hopefully that answers your question first part, Phil. And then on the pivotal enrollment criteria. So we're actually expanding it a bit. Well, we didn't narrow it. I think one of the striking things again about the data set was, as we've said many times, the consistency of the response. So I don't feel like there's a population that needs to be excluded here. So we had a 6 and older is entry criteria for the Phase II. We've decreased that to 4 and older on these tumors, of course, can occur in younger children. We've already had requests for compassionate use in the children who are younger than the age of 6. So that need is clearly there. We'll preserve the -- you must be 6 months out from your injury with the idea that these patients need a little bit of time to settle, get their other hormonal treatments stabilized and the like. There's no age restriction on the upper end, and we had adults in their 20s in the first trial, and I think that will still basically be the range, but we didn't limit it there. In terms of weight criteria, similarly, you have to -- have had a documented weight increase after your BMI, but we don't require a specific number. We're trying to very much leave this to the clinician to make the diagnosis. And that growth chart that you saw from Dr. Roth's patient is quite typical in a sense. I mean that was severe and the steepness of the rise there. But this steep rise is highly characteristic. And so the idea that it's a clinical diagnosis, a pattern diagnosis, and we want to leave that to the physician. So no specific requirement for the amount of weight that must be gained in that. You have to be obese by definition with a BMI greater than 30 or greater than the 95th percentile of your any child.

That's very helpful. Congrats again on the data. They continue to look great.

Our next question comes from Adam Vogel with Wells Fargo.

Great data and congratulations. How do you the Phase III trial to enroll in terms of speed relative to your other past trials? And do you think you'll be able to leverage many of the sites you've used previously from those trials as well.

Yes. So it's a good question. So yes, I do think it will enroll much more quickly Things that will dictate time are more of the administrative logistics just getting trials set up and getting through IRBs and the like. But the actual patient enrollment piece -- I mentioned this on prior calls, and it continues to be true. As we talk to specialists in the area just everybody, we talk to has multiple patients, not just sites where they might be trial sites so talking about just these patients are -- they're in these practices. They're seeking help. And so I do think the demand and the ability to enroll patients will be significantly faster from that standpoint. With regard to the sites we'll be using, our expectation is we'll use all 5 sites that were in our Phase II. These sites and Dr. Roth can speak to his own experience here, they enrolled a few patients in our Phase II to get up to 18, but they all have multiple other patients. . Dr. Roth, if you have any...

Yes. I think what will help is the large age range. So I'm glad -- as a clinician I'm really glad to see that we can offer that to a larger portion of our patients. And also that there are different tumor entities included not just patients with craniopharyngioma, which is the most common tumor that can cause this problem. So I think that it's reasonable to have this goal of enrollment.

Adam, do we answer that?

Great. Yes. Congratulations again.

Our next question comes from Dae Gon Ha with Stifel.

Let me add my congrats on the data. It looks very robust and consistent. Maybe a short question for Dr. Roth, when we look at that particular standout patient, just wondering how representative is that patient when you compared to the rest of the hypothalamic obesity patients under your care, having multiple surgeries seems pretty burdensome and pretty exceptional, but I just wanted to get your take. And then for the team, just thinking about Phase III, I guess any thoughts on, number one, the number of previous surgeries that you might want to include as part of your exclusion criteria to make sure you enrich sort of the magnitude of BMI reduction going forward? And then two, if you can clarify for me. So Phase II now includes up to 8 weeks of dose titration phase. If we revisit Phase II, I mean, how does that jive with the patient experiences there. And how many of the less than 6-year-old actually managed to get up to 3-milligram rather than between 1.5 and 3?

So I'll take the first question here. So regarding this patient, he's a little bit, let's say, an unusual patient in a way that he has a different diagnosis. Hematoma is rare. Most of the patients we take care of, and we have in our grand tumor clinic more than 40 that have hypothalamic obesity. Patients with craniopharyngioma, they understand very well the treatment, they are very motivated and also their parents here. In this patient, you mentioned he has severe autism, he has several other medical problems that can hamper the result of such a trial. But I think it's very important to include those patients because there is no way to treat them. And so even if we have less strong response to medication, it has been a success. In some patients, we say, actually, if we can stabilize the BMIs and do not reaching reduction of BMI. That is already the success because they have this steep increase of BMI before. So if you can stabilize the BMI to a certain point, that is typically already regarded as a success of treatment. And so I think -- and I'm hopeful because he is now losing weight. So I'm hopeful that this will be successful for him.

Yes. Perfect. And maybe just to add from the trial, Dae Gon, we had -- across the 18 patients, there were several patients who had multiple surgeries. So that fact alone, I would say, is probably not necessarily a negative risk factor for response. And we also had the 3 hematomas and interestingly, the 3 hematomas so they're Dr. Roth patient. The patient who had the greatest response, the 6-year-olds who go back to the waterfall plot, the patient who was farthest on a little left there, who lost 37% at 16 weeks. That patient had a hematoma. So it's not that the tumor per se or the number of surgeries per se. I think as Dr. Roth has highlighted, there may be, again, just a sheer amount of damage that has done and the like, which may change, of course, the ability to respond at some point. But there's nothing there that guides us out of the first 18 patients that says this is a group that we should exclude or be careful about how we manage. So again, we've gone broad there. . Your question on dosing. So the dose escalation period, it was variable in the sense that -- so everybody got to more or less, they're 3 megs within the 16-week period. As a rule, 8 weeks, what we allow is -- so you either start on 0.5 to -- for the youngest or 1, and we're dose escalating every 1 to 2 weeks to get up to 3. So 0.5, 1, 2, 3. So if you took 2 weeks, it would take you -- for each step it will take you the full 8 weeks. We've also built-in flexible dosing. So our goal is to get to a therapeutic dose. By definition, that is the maximum tolerated dose. So if you're -- if you got to 3 and you're struggling to tolerate 3, you could be maintained on 2 and or just go more slowly. But that's the range. The vast majority, if not all patients, we fully expect to be at target by 8 weeks. What we've tried to do is to design the trial in a way which minimizes the risk that patients stop the drug for the tolerability issues, which happened early on in the trial. We've got now vast experience as we have increased our commercial opportunity and the treatment of patients in that sphere. And it's clear that if you're struggling the drug a little bit, you dose decrease and then more slowly dose increase, and that's been extremely successful. So we've tried to build that strategy into the Phase III trial.

Our next question comes from Corinne Jenkins with Goldman Sachs.

Maybe the first question for me for the doctor. Just in your experience, how do patients fare on the GLP-1s or other therapeutic options you might be using in this population? And how does that compare to what we're seeing with setmelanotide here?

Yes. We have used different drugs before stimulants like methylphenidate. I was actually the PI together with Dr. Abuzzahab on the trial -- clinical trial testing in GLP-1 receptor agonist. In that trial, we found moderate responses. Some of the treated patients actually gained further weight during the treatment. And then we -- there is also an oxytocin trial, and that trial was also not very strong. The changes were not significant compared to placebo. So I think as I've mentioned before, the strong response that we are seeing here is really unique. I've not seen that before. And so that's very helpful. .

Great. And then maybe just one more for me. We did see, obviously, a pretty nice deepening of response on a mean basis in that open-label extension days. I'm just curious kind of what portion of patients are continuing to see response. Is it majority of them? Can you just contextualize that for us?

Yes. I think what's interesting is there's -- so essentially, all patients are continuing to see a response. Some patients have plateaued. For example, that 6-year-old is basically at a normal BMI. There's no desire for that patient to lose any more weight. There's a couple of patients there who had a began to gain some weight. And on querying it was very clearly related to a change in their behaviors where the family has stopped paying attention to their management, if you will, of their child eating and the child had started to eat again. And it goes back to hunger being -- there's many parts of hunger. One is the drive to eat because they are literally hunger. There are the behaviors that are ingrained over time. And those need to be modified as well. And so as those get modified, then there's a return to efficacy. So there is noise in that, but the answer to your question is the majority virtually -- essentially all patients have continued to have a response.

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

Two for Dr. Roth. One, was wondering if you could comment on the overall safety and tolerability profile of setmelanotide in HO patients given the Phase II data to date and sort of maybe describe the tolerance level of HO patients under your care and how that fits to what the data has shown to date? And then secondly, given the totality of the Phase II data to date, what percentage of your HO patients would you use the drug in?

Yes. Thank you for these questions. First is safety data. We did not have any significant problems during the treatment with our patients. That was -- what we saw is hyperpigmentation in our patients. They liked it to some degree, actually, but it was very remarkable. There is a strong hyperpigmentation. There are some patients who drop gastrointestinal problems like nausea, but that was mostly transient, and it was not a problem. So I don't see -- currently, I don't see any issues with safety right now. The second -- the percentage of patients that we could potentially treat with this drug is, I think, relatively high. So I think in those patients who have this very strong weight gain, they would be very motivated to have a drug like this. The one limitation is the injection is done once per day. So in some of our children, that could be a limitation. I did not see that in our patients we treated so far. But -- and we have also, for instance, patients in our endocrine clinic who received daily growth hormone injections or several times per day injections of insulin. So that is not a complete limitation, but it would be nice enough to have maybe something in the future that doesn't meet everyday injections. But it is tolerated, it's not a limitation that prevents us from using this drug.

Our next question comes from Michael Higgins with Ladenburg.

I appreciate the opportunity to ask some questions here. A couple have gone on the Phase III before a second that may be best for the KOL as well as yourselves. On the Phase III, I noticed in the slides in your comments that the secondaries are including patients over 18 -- 18 and over, 12 and over, the average age in the Phase II is around 15. Yes, it was around 15. If you could help us understand why you're highlighting those secondaries and then a couple more on the Phase III.

Yes. The challenge with measuring hunger in these scales is that you need to be at a certain level of development to be able to participate and answer them. So that's why the cutoff as well. We tried to divide; obviously, children are growing. And so division between 18 over and under, of course, is related to that. But the hunger issue, the 12 cutoff is really related to the ability to participate in the questionnaires and the analysis of the hunger.

All right. Can there be a dose change during the study period and any interim assessments expected?

There can be a dose change. So again, as I said earlier, the goal is to have flexible dosing to ensure maximum tolerability. So yes. So that's...

And on the interims?

Oh, sorry. No, there will be no interim.

Okay. And then last on the Phase III design. Any potential for European sites? Have you had or plan to have discussions with European regulators? How is the outlook there?

Yes. So we have -- we started a parallel process, so we're engaged with the EU. They're a little bit behind the FDA, so we don't have their formal feedback as of yet, number one. And two, we will have a new sites. We'll have probably the majority of the sites in the U.S., but we will have some small number of European sites.

Okay. That's helpful. And then lastly, to help us assess the adverse events that we're seeing here. Do you have any data on the HO patients' health outcomes of untreated higher BMIs increased weight, et cetera?

Maybe -- I mean, I'll make an introductory comment and Dr. Roth can add on here. I mean there is data of patients who have these craniopharyngiomas who go on to develop hypothalamic obesity, do well -- do worse, have a shorter -- somewhat shorter lifespan and have higher degree of cardiovascular complications and those that don't. I don't know this...

I think it's very clear they have higher risk for cardiovascular disease. And it's not just related to the extreme obesity. It's also something that is distinct problem for those patients.

Our next question comes from Tazeen Ahmad with Bank of America.

Congrats on the updated data. Just wanted to get a sense about using percent change in BMI as the primary endpoint for Phase III. Why choose that versus percent weight loss? And then I have a couple of follow-ups.

Yes. I mean this is a bit of the curse of rare diseases. So patient trials -- in patients with obesity run multiple trials for all the different age groups, and you have adults only and teenagers, only, et cetera. So we are mixing children age greater than 4 with adults. And so BMI is an imperfect correction for that, but it is much better than just using weight. And from our prior experience that weight create real problems, particularly in the group that's growing and expected to gain weight. So it's just it's a practical compromise. I think given the results we're having the robustness of it, even though it's an imperfect measure, I think we have a high level of confidence that it's the best measure and it will show the difference. .

Okay. Are you looking at weight as one of the secondaries?

Oh, yes. Of course, yes. The weight will be in patients age greater than 18. So once you've stopped growing, but for the kids, we'll look at multiple things in addition to BMI. So we'll look at BMI-Z, which corrects for that growth, also imperfect when you get into the teenage years and increasingly where the field is going, and Chris you may have a comment on this as using the percent of the 95th percentile, which is felt to maybe be a better reflector of exactly how that population is doing for that -- for their age.

Got it. Okay. One question for Dr. Roth, if I could. In terms of the nausea and the vomiting. I think you may mention that for some patients, it help them not think of food, obviously. But if you were to compare the incidents of nausea and vomiting seen in this study just relative to other types of drugs that you might have prescribed for patients for weight loss, let's say, GLPs, how tolerable are the side effects in a real-world setting for your patient population? Like for example, what percent of your patients on GLPs for weight loss drop out?

Yes. So we see that more in patients treated with GLP-1 receptor agonist. And in some of these patients, it was limiting here in setmelanotide in those patients I've seen that it was not a limiting factor. And so to answer your question, I think we see that more often and more pronounced in patients treated with GLP-1 receptor agonist.

Are you saying that in studies or in a real world setting for GLPs?

Both.

Okay. Can you just -- can you give us a sense of what proportion of patients would be pediatric versus adult for HO?

My perspective, I think the pediatric world is really looking up to this trial. And therefore, I guess that there will be more pediatric patients, including adolescents than adults, but I could be completely wrong. But I see that the families are very motivated to participate in trials. So that might help also with enrollment.

Tazeen, I don't know if this is at all relevant, but -- we thought the same thing in DBS that probably because we are focused there and maybe the kids are more actively engaged and a little more visible. But we thought there would be a higher percentage of kids and what it's turning out as we get into a commercial setting is it's pretty evenly split between kids, adolescents and adults. So as Christian said, this idea that once the therapy is available, some of these adults may come back and seek help in ways that we wouldn't necessarily expecting.

Our next question comes from Jeff Hung with Morgan Stanley.

This is Mike Reid on -- for Jeff Hung. So looking at the LTE, it looks like 13 out of 14 patients reached week 13, but we saw even greater BMI reductions for these 5 patients who continued out to week 25. So we had 2 questions here. First, can you provide us with any details on what led to those 8 patients who are presumably already showing improvements dropping out between weeks 13 and 25? And second, following end of treatment, were you able to track these patients? And did they maintain the reduction or regain weight or hyperphagia?

Yes. Thanks, Mike. Yes, very clear. So the 13 patients, that's the 13 that have reached their 13 weeks. The first LTE visit 1 patient has not. Of the 5 who reached the 25 week, the others have not reached that point yet. They haven't dropped out. They're all still in the study. So there's been no there's been no drop down. And then you had 1 other question there. So I just -- I am trying to thought...

No, then I guess you can disregard. I want to know whether they would regain their weight in hyperphagia...

The only comment I was going to make there. Of the 4 that did drop out and I'd mentioned this on, I think, on the July call or the August call, the woman who had lost 7% and regained a little bit -- after she lost 7% in 4 weeks and regained a little bit at 8 weeks. We did have a 20-plus week readout weight for her and BMI. And her BMI had -- she regained all of her weight and had regained 14% more. And so -- and we don't have as good for the other patients. But this idea that this is a replacement therapy. So it's not that you correct -- you used the drug for a while and you correct behaviors and then somehow, you're able to maintain your weight without the drug. It's really -- there's a deficiency here in theory of their endogenous ligand, alpha MSH and setmelanotide replacing that. And as long as you're on the drug, then you're likely to be physiologically more normal. When you come off, you return to your former physiologic state.

I'm showing no further questions at this time. I'd now like to turn it back to David Meeker for closing remarks.

Great. Well, thanks, everybody, for joining in this morning. Obviously, we're, as I said, I'm incredibly excited about the progress we're making, the opportunities here and the difference, I think, we're going to make for patients with HO. So we look forward to updating you, and we'll talk to you again in a week. Thank you.

Thank you for your participation in today's conference. This concludes the program. You may now disconnect.