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

And thank you for standing by. Welcome to the Rhythm Pharmaceuticals Conference Call. [Operator Instructions] 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, with Rhythm Pharmaceuticals. Please go ahead.

Yes, thank you, and thank you all for joining us today. For those participating via the conference call, there are accompanying slides that can be accessed and controlled by going to the Events section of our Investors page on our website at ir.rhythmtx.com. This morning, we announced positive interim results from our Phase II clinical trial evaluating setmelanotide in hypothalamic obesity via a press release, which is now available on our website. On the conference call today, as listed on Slide 2 on the agenda, are Dr. David Meeker, Rhythm Chair, Chief Executive Officer and President; Dr. Jennifer Abuzzahab, a pediatric endocrinologist at the McNeely Pediatric Diabetes Center and Endocrine Clinic at Children's Minnesota, where she is a clinician in the comprehensive neuro-oncology unit. She is an expert in neuroendocrine disorders such as radiation-induced hypopituitarism, hypothalamic damage and hypothalamic obesity. Also, Dr. Abuzzahab is a member of the Raymond A. Wood Foundation's Scientific Advisory Board and she's an investigator on this Phase II clinical trial. And lastly, Hunter Smith, our Chief Financial Officer, will join us for Q&A. Now moving to Slide 3. I'll remind you that this call contains remarks concerning future expectations, plans and prospects, which constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual or quarterly 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 as of any subsequent dates. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to David, who will begin on Slide 5.

Thank you, Dave, and good morning, everyone. Thank you for joining us this morning. I assume you have all read the press release and understand why we are excited to provide this update today. Patients with acquired form of hypothalamic obesity represent a potentially transformative opportunity for Rhythm. So we'll be presenting data on 11 of the 18 patients enrolled in our Phase II study. I remind you, as you see on Slide 5, that we are starting with an approved therapy IMCIVREE for multiple indications. In June, as you know, we were approved for BBS, and we very much look forward to updating you on our progress at our next earnings call. We've been really extremely happy with the acceptance we are seeing in our international markets and are looking forward to an EC authorization for BBS this year. But today, we're here to talk about a significant expansion opportunity here for the potential opportunity for setmelanotide. And equally important, what this data represents is a very strong confirmation of the unique biology surrounding setmelanotide. Not all forms of obesity are the same, not all treatments for obesity are the same. And as with most diseases, you want to match the disease with a treatment which targets that disease. So moving to Slide 6. Let me provide you with a brief introduction to the -- to hypothalamic obesity before I turn the call over to our expert, Dr. Abuzzahab. This is a true unmet medical need with a population of patients who all suffered without a consistently effective therapy. The community is well organized and the patients are identified. This is a clear point of differentiation from the other diseases we have worked on who either require a genetic diagnosis and/or a clinical diagnosis by an experienced physician who recognizes the syndrome. But the majority of patients with the acquired form of HO, this is a complication of the treatment for a benign tumor. They know who they are. They are engaged with the health care system. The patient organization, the Raymond A. Wood Foundation, has advocated effectively for better therapies, including having held a listening session with the FDA in the past year. The biology is well understood and as you will hear from Dr. Abuzzahab link to the impairment in the MC4 pathway. Therefore, it was not a surprise that setmelanotide shows activity. And finally, as noted, there are no approved effective therapies for this disease. Moving on to Slide 7. Here's the headline, as you've seen from the press release, all 11 patients lost greater than 5%, including 2 patients who discontinued during the trial period. The mean BMI decrease was 17.2%. I want to remind you that we are used to seeing weight and BMI numbers at 6 and 12 months of follow-up in these kind of trials, but this was a 16-week trial, which included the dose escalation period, so a relatively short period of drug exposure. I will be presenting a full summary of the results following Dr. Abuzzahab's presentation. On Slide 8, this is our familiar mechanism of action slide, and just to remind you that setmelanotide is a MC4 receptor agonist. The pathway in the MC4 receptor have been intensively studied, it's not random. One aspect of its MLA, which we have not focused on as much in the rare genetic diseases of obesity we have studied is the energy expenditure component. We've been more focused on the MC4 receptor's impact on hunger. And you'll hear more about why that effect may be disproportionately important in this population. Slide 9. So the HO population represents a very significant opportunity. These numbers are U.S.-based epidemiology estimates only, where we believe there are about 5,000 to 10,000 patients suffering with HO today. The most common cause is a benign tumor, either causing HO itself as it grows or resulting in HO as a complication of the therapy for the tumor -- or the therapy for the tumor which the most common benign tumor is a craniopharyngioma. Multiple other benign tumors as well as some nontumor-related causes may result in injury to the hypothalamus, and consequent HO, which is believed to occur in approximately 50% of patients with one of these injuries. The annual incidence of HO is about 500 cases per year. One striking difference, again, from the rare genetic causes impairing the MC4 pathway is that most physicians we talk to have patients under their care with HO, supporting the observation that this is a reasonably sized rare disease population who are diagnosed and are seeking help. And with that, I will turn the call over to Dr. Abuzzahab.

Good morning, everybody. We'll move on to Slide #11 just to give some background for a specific patient journey. One of my children who has hypothalamic obesity that we know that there's damage to the ventromedial nucleus of the hypothalamus and often due to craniopharyngiomas but other suprasellar tumors as we've mentioned before, even surgeries that can damage the hypothalamic pathways or radiation. The strongest increase in rate is seen really within the first 6 months following the injury to the hypothalamus with unrelenting and persistent recalcitrant weight gain. We suspect HO based on the tumor type, the tumor position and then the rapid onset of obesity following therapy. And we can often see on MRI some of the damage to the hypothalamus [indiscernible] in the third or 6 month following surgery once some of the inflammation has decreased. And really, there are currently limited treatment options. The current pharmaceutical array they have that treats general obesity is not often successful for our hypothalamic population or a population of hypothalamic obesity by maybe 20% or 30% effectiveness in things that are 80% to 90% effective in the general obese population. Moving on to Slide 12. This is a diagram of pituitary and hypothalamus. And I think on a very simple case I'd like to think about the pituitary kind of as a cell phone and hormones you can see there -- those little dots as the text messages. And then the hypothalamus is the 5G or LTE network that integrates all these vision and afferent signals. This yellow bar that you can see that runs from the pituitary straight up into the hypothalamic area demonstrates the Rathke's pouch pathway. [indiscernible] are very specific to nontumor that arise from the remnant of the Rathke's pouch and you can see that they follow that yellow path and all the way up and into the hypothalamus and specifically, that very vital ventromedial nucleus that contains the agouti-related peptide and neuropeptide Y or the -- sorry, the orexigenic pathways and then POMC and CART, which are the anorexigenic pathways and it just destroys those pathways. Other suprasellar tumors that we mentioned can also cause this kind of destruction, gliomas, germinomas, collagenomas, astrocytomas or hamartoma that they arise in the suprasellar area and then invade into the hypothalamus or the hypothalamic damage from surgery. This results then in deficiency of the , melanocortin-4 pathway causing reduced energy expenditure, varying degrees of hyperphagia and rapid onset obesity. Slide 13 then is representative like close up of that [ VM ] nucleus. Again, you can see this balance between the orexigenic and anorexigenic pathways. The tumor is now represented by a large golden ball that is invading and disrupting the transfer [indiscernible] like PCSK1 [indiscernible] POMC to the various melanocortin ligand, which feed into melanocortin-4 receptors. And you can see then cause decreased energy expenditure and increased energy intake, which is just a vicious cycle. Moving on to Slide 14. This is an MRI of one of my patients. You can appreciate hopefully the large mass directly above the pituitary. You can see the pituitary sella with a flattened area and then large mass is above and the flattening of the corpus callosum. Moving to Slide 15. You can see it from a different view in a different weighted image, where now the tumor shows up in a lighter shade of gray. And again, you can appreciate that it's so large that it's actually pushing the brain slightly off of midline as you can see. This has been the growth curve of one of my patients on Slide 16 with hypothalamic obesity, who is diagnosed with craniopharyngioma at age 4.5 or 4 years 8 months. He had surgical excision only, and you can see that almost immediately after the surgery. He goes from a BMI that's at the 75th percentile or in the normal range to a BMI that is well above the 97th. These growth curves have [ age ] along the X axis and then weight or BMI on the Y-axis. I mean if you step back and kind of think about the growth norms are for an adult, we'd like to have a BMI less than 26 for children that relates to about the 85th percentile and obviously child greater than 30 for BMI, which is about the 95th percentile for a child because it does -- BMIs do change with age. He was waking at night to forage for food. The family has locked the cabinet. And he has become really, really sedentary since his tumor. He had tumor recurrence around age 8 and had -- I'm sorry, at 6 years they mentioned at age 8 he had a brief period of weight loss when the family tried a lower carbohydrate diet. They were unable to maintain this. And during this period when we had -- when he was on the lower carbohydrate they were also trying to get them to move more because he's just so sedentary. They would take them out on walks and they sent me a picture of him on a walk one day, and he's holding a little cup in his hand. So cute that he is out for a walk, what's in his hand and they said, oh, that's the milkshake. They didn't really go into further details in trying to figure out how that sort of fit into his low carb diet, but this is just his saga. And he continues -- again, you can see the weight gain. And we'll move on to slide 17. This is the same boy, just further progression. The first curve is now a growth curve, so it has age on X axis and height on the Y axis. And you can see that he's actually growing well. So the increase in BMI is not due to weight gain without height gain. At age 14, again, you can see a slight decrease in weight for about 6 months. He was on a GLP-1 agent, he did lose a little bit of weight but really couldn't tolerate the medication due to significant side effects. His peak BMI was 39.5 and his weight was 120 kilos when he was enrolled in the setmelanotide Phase II study. And you can see here at Page 16, that he has just had his remarkable weight loss. He lost 10 kilos in the first month and has been steadily using in the extension phase of the study, as you can see. And in addition, I think almost as remarkable as the weight loss is the change in his energy and his demeanor, not only is the family no longer locking cabinets because he's not getting up to forage for food at night. But he also is just more active and engaging. You know, you remember he needed to be bribed with milkshake to take a walk. He would take 2 minutes to walk from his chair to the exam table in the room because it just was so much effort to get up. And now he is jumping up to show his items in his backpack during clinic visits and he has a little toy that has a ball and a string. He's like throwing it all over the room and gathering it back. It's just amazing. And even teachers have noticed differences in his behavior and interaction. We move on to Slide 18. This is just a reminder that due to aggressive growth alarm [indiscernible] craniopharyngiomas have invaded the -- that have invaded the hypothalamus are associated with a higher rate of hypothalamic obesity following tumor removal. We've a great study looking at 21 patients who didn't have hypothalamic involvement at diagnosis. And you can see in the left-hand side of the slide, then that the BMI remained fairly constant for -- throughout the years after diagnosis. The first gray box is 8 to 12 years after diagnosis and the black class is over 12 years from diagnosis. But mean BMI is fairly consistent. And you can contrast this with the right side of this graph, which shows 43 patients who have hypothalamic involvement at diagnosis in the white box, you can see already at the 8 to 12 years from diagnosis and consistently in the black box at 12 years from diagnosis there is dramatic increase in BMI. And this is represented in standard deviation scores, which I think is remarkable. Also that there is a 4.29 standard aviation increase on the mean -- or median for increase in BMI following diagnosis. So it really is quite an aggressive tumor and really destroyed these pathways causing decreased energy expenditure and increase in energy -- appetite intake. This is a twofold problem. I think in addition, there's probably maybe a trifecta in that a lot of the kids have some memory issues if they've had radiation. And even if they just had a meal, they're like, "Oh, I'm so hungry. I'm going to go and have another meal because they sort of forget that they just ate, a triple threat. We can move on to Slide 19, which is just a summary. So that, again, due to the damage and an inability to integrate the anorexigenic and orexigenic pathways and damage to this MC4 pathway hypothalamic obesity is refractory to the treatments that are often beneficial on treating general obesity, such as lifestyle or diet modification. There is primarily no pharmaceutical agent that's been approved or even generally effective in late-stage trials that have 20% effectiveness. Bariatric surgery has been shown to be effective, but it's not as effective in patients with hypothalamic obesity as it is in patients with general obesity. And in addition, it permanently reverses or impairs normal physiologic pathways or processes [indiscernible] causes permanent nutritional damage, which we'd like to avoid in pediatric patients due to effects on bonds and those vital nutrients. So really I recommend our limited in our options. There's new surgical techniques that are hypothalamic sparing using transsphenoidal surgery that are promising, but have not completely ceased to cause hypothalamic obesity perhaps due to the tumor itself. And that concludes my portion. We'll move on to Dr. Meeker. Thank you.

So now I'll present the results of the clinical trial. So on Slide 21 is the trial design. This was an open-label 16-week trial with 2 different dose escalation regimens based on the age of the patient. The primary endpoint was the percentage of patients decreasing their BMI by 5% or more at the end of 16 weeks. The enrolled population included patients who are more than 6 months out from their surgical treatment for the tumor and who had a documented weight gain of 5% or more from that time and a BMI of 35 or greater -- or in the case of patients less than 18, a BMI Z increase of greater than 0.2 and a weight equal to or greater than the 95th percentile. In Slide 22, we have the disposition. So 18 patients enrolled in the trial. All 18 patients have completed their 16 weeks, although we do not have the efficacy data on all 18. Two patients discontinued due to an AE during the 16-week clinical trial period. One patient completed the trial but chose not to continue into the long-term extension. And I'll provide greater detail on these patients at the end of this section. One patient had documented noncompliance and was discontinued. So 14 of the 18 are continuing on therapy at this time. And today, as I said, we are speaking specifically to the 11 patients who had completed the trial by the prespecified main cutoff. So on Slide 23, you see the demographics for these 11 patients. Their mean age was 14.6%. Of note 9 of the 11 were less than '18, which speaks to the demographics of this underlying benign tumor etiology. The mean BMI for the group was 38.7% with a range of 23% to 44% and the BMI in the low end of that 23% was in a 6-year old child. So moving on to 24 with the results. There was a mean decrease in BMI of 17.2% with a mean decrease in weight of 15.8%. The 9 patients who completed the full 16 weeks on therapy showed a 19.5% decrease in BMI on average and a 17.8% decrease in weight. On Slide 25 is a waterfall plot in the BMI percent decrease. The 9 completers are in blue with results which range from minus 10% to minus 37% [ increase ] in the 2 patients who discontinued early are in gray. As you can see, there was a solid response to therapy across the whole patient population. Of the two who discontinued, the first patient decreased their BMI by 7% by 4 weeks of their last visit on therapy. At the next visit, week 8, now off therapy, they had started to regain with a BMI of 6.8 -- minus 6.85%, and those numbers are compared to their baseline BMI. The second patient decreased their BMI by 8.2% at week 13 and had regained weight off therapy at week 16 with a BMI of minus 6.7%. So on Slide 26 if you look at the weight. So even though the completer group consisted of the 9 children, where weight isn't always the optimal measure because these children are growing and should be putting on weight, in this case, over the 16-week period they all lost weight with a mean decrease in rate of 17.8%, representing almost 40 pounds on an average. On Slide 27, the 9 children started with a dramatically elevated BMI Z of 3.56 and this is analogous to the BMI standard deviation number that Dr. Abuzzahab has shared. So their starting BMI Z was 3.56 and it decreased by meaningfully -- clinically meaningful 1.1 points. On Slide 28, with regard to hunger, hunger can only be reliably assessed using the Visual Analogue Scale from 0 to 10 in patients 12 and older who are able to provide that data and information individually. Of the 7 patients equal or older than 12 who completed the trial, with a baseline value of 7.8, they had decreased on average by 2.66 points. Of note, both the starting score and the average point decrease is consistent with what we have seen in the other populations we have studied. Slide 29, safety. So reassuringly safety was perfectly consistent with what we have seen in the other patients we have treated. There were 2 serious adverse events, one due to C difficile colitis, which was judged not related, and one due to an elevation in liver transaminases, which was related. There were 2 adverse events leading to discontinuation during the trial period, which I will discuss in the following slide. The most common AEs were the GI-related complaints, which tended to be mild in severity and transient. So on Slide 30, here's our disposition slide. 2 patients discontinued during the trial period due to AEs, as I noted. The first patient stopped at week 13, secondary to unhappiness with hyperpigmentation. This is a complication we've seen in other studies. The second patient was asymptomatic but noted to have an increase in her liver transaminases without an increase in her bilirubin. Of note, this is the only liver-related AE we have had with over 700 patients exposed in our clinical development program. So the drug was stopped. The enzymes decreased, the patient was rechallenged and the enzymes went back up again and a temporal relationship to the administration of the drug. The drug was then stopped again and the liver enzyme transaminases normalized within 1 week of stopping the drug. There were no other signs and symptoms. Of note, this patient did have a complex background with a history of hepatitis A exposure, a low-level positive ANA and documented liver steatosis on ultrasound. The third patient completed the trial period with a 10% decrease in her BMI in 16 weeks, but elected not to enter the long-term extension. This patient also had a complex medical history with a chronic history of nausea, entering the trial, which worsened on therapy. This was also the patient who had C. difficile colitis during the trial period but managed to stay on drug through that complication. So moving to Slide 31. In summary, patients with HO have no approved therapies as you've heard. They have no therapies which consistently work in this disease or that specifically addressed the underlying disease state. We're really encouraged as you might guess, both by the consistency and magnitude of the response we've seen with setmelanotide. It's a completely addressable patient population with 5,000 to 10,000 patients living with this disease in the U.S. and equal or greater numbers outside the U.S. We know who they are. These results offer further confirmation of the strategy we have been pursuing a platform and a drug where step by step we are working to understand all the different population -- patient population with impairment in the pathway who might benefit from setmelanotide. With that, we plan to present the full data at a fall meeting. Our goal is to get in and get our end of phase II meeting with the FDA as soon as possible with the objective of beginning a Phase III trial early in 2023. And with that, we'll open it up for Q&A.

[Operator Instructions] Our first question comes from Derek Archila with Wells Fargo.

Congrats on the data. Just on -- just 3 quick questions from us. I guess, first, David, on the IMCIVREE data that you have to date, again, saying that you have not seen any increase in LFTs, just remind us how many patients and what's the longest patient you've had on IMCIVREE thus far?

Yes. So we've had no other clinical AEs related to increase in liver transaminases. One, the number of patients is 700-plus. That does not include our now growing commercial population where this complication did occur in most cases, that would be reported in -- so over 700. And then the longest period that a patient has been on drug, I think we are out for the earliest patients treated with biallelic POMC deficiency and Leptin receptor deficiency at 5 to 6 years.

Got it. Perfect. And then just 2 quick questions for Dr. Abuzzahab. Thanks for being on the call and a great insight into these patients. So first, I guess, would you say that these patients are easier to identify than Bardet-Biedl? And then in your practice today, in terms of the HO patients you see, what percent do you think would actually be candidates for treatment like IMCIVREE?

Those are good questions. I think in general, they're much easier to identify than children with a genetic syndrome because they've had -- in my patient population anyway, they've had a tumor and so I'm seeing them for other endocrine disorders as a consequence of that tumor and then recognizing the hypothalamic obesity often immediately after surgery while dealing with the other endocrine issues, whereas patients with some genetic disorders like Bardet-Biedl are also -- are usually seen by their primary care providers and only referred to genetics or to endocrine if someone suspects the underlying genetic disorder. So I think the pathway to getting diagnosis is a little bit longer. Tumors are difficult to ignore. And in our population, probably 80% of our [indiscernible ] have hypothalamic obesity. So it's really quite a few.

And would you -- and are those all candidates for IMCIVREE? Or would there be specific patients like within that 80%?

I would say like I had 3 patients in the Phase II study and they all lost weight on the medication, which I haven't seen with any other medication trials that have -- from the FDA-approved medications that we tried for treatment of obesity. I think we would probably try everybody on it if it was approved.

Our next question comes from Philip Nadeau with Cowen.

Congratulations on the data. First, a couple for Rhythm and then one for Dr. Abuzzahab. First, on the efficacy data, just what was most striking to us was the consistency of the effect on all patients. We've been made to believe in the past hypothalamic obesity is a very variable condition. And so the consistency was particularly impressive. What does management attribute that to? What about [ ancillary's ] mechanism would be consistently active across this diverse patient population.

Yes, it's a great question. So there's a bit of a black box to some of this, not fully understand, but I think there is a unifying hypothesis and we were struck as you were by this overall consistency. So as Dr. Abuzzahab has described, there is disruption, in some cases pretty significant destruction in that area of the brain and, obviously, including the hypothalamus. The pathway itself, the area is destroyed. Arguably some, many, maybe all of the MC4R receptors that are in the hypothalamus may be destroyed. What's interesting is that the MC4 receptor is not limited to the hypothalamus and there are receptors outside and those receptors outside statistically ones in the spinal cord mediating play a disproportionate role in managing the energy expenditure side of this equation. These are receptors linked to the autonomic nervous system. And so it's highly plausible that given the striking effect, I think we're seeing on the energy expenditure side of the equation that may not just be the resting energy expenditure. Dr. Abuzzahab described the child of hers who post developing this complication became much less active. And then with treatment, the weight loss reduction and the hunger who knows all the factors, but subsequently became much more active in her overall activities of daily living there. So I think the take home here is, I think, part of that consistency we're seeing is the effect we may be having on MC4 receptors outside of the hypothalamus. And one last thing, Phil, about that, another question that's come up as a side note, did we study a population that was perhaps not representative of this over age old group? I don't think that's the case. 18 is a small patient number. So of course, we can't cover probably every possible scenario. But we did have a very significant mix. We had multiple different tumor types, craniopharyngioma, astrocytoma, hamartomas, as etiologies coming in, number one. Number two, the location of the tumor. We had tumors which involved unilateral parts of the hypothalamus, tumors that involved bilateral parts of the hypothalamus. And obviously, a range of ages as well. So I think we've done pretty well in getting a sense that whatever the background heterogeneity may be, this effect looks quite consistent.

That's really helpful. Second question is on the Phase III. You suggest maybe a Phase III could begin in the first half of next year. We appreciate you starting to have the discussions with the FDA. What preliminarily would you expect the design to look like?

Yes. I mean -- so I'll give you sort of the general sense of interacting with part of that division. As we know, number one, absolutely convinced this will require double-blind randomized controlled trial. That's been historically the feedback we and others have received. Second, as a rule, they like to see 12 years of -- 12 months of exposure. So from a length of trial, that would be an expectation going into that part of the conversation. With regard to size of the trial, that question has been asked. And given the size of the effect we're seeing, it does not require a large trial approved efficacy. And so the discussion we'll be having with the FDA and the like is what is the size of the safety database, which they would like to see again to support the safety in this population. The good news here is, again, we're not starting with a new drug. We're starting with a drug that's in fact, approved. And of course, has a very significant data -- safety data set coming into this discussion. So we'll see where that ends up. But those are our preliminary thoughts with no input, of course, yet from the FDA.

That is great. And one last question for Dr. Abuzzahab. You mentioned that the current pharmaceuticals are not ideal, not all patients respond and the response is less than what you'd expect for general obesity. Could you maybe elaborate on those comments? What typical weight loss would you see for the currently available pharmaceuticals in your patient population? And what proportion of patients do respond to ?

So I try -- I tried some of the commercial available medications so especially focusing with GLP-1 agents since they really have the best weight loss in the general obesity population and Qsymia, which is a combination of topiramate and phentermine. And I guess maybe 20% of my patients respond to it or can tolerate it. And for those who do, I have a handful of kids who are actually had -- having reasonable benefit and he's been on GLP-1 agent for several years now, but that's a small fraction of my patients with hypothalamic obesity because the majority of them, 70% or 80% just don't respond.

Our next question comes from Corinne Jenkins with Goldman Sachs.

So craniopharyngioma seems to be pretty split across both pediatric and adult populations. So I did note that it seems that the study is skewed towards maybe younger population, if not pediatric. And so I'm just curious like why that might have been? And if that's going to continue to be the case as you expand the study into Phase III? Or you'll be studying like a more adult population?

I'm going to have Dr. Abuzzahab comment on what she thinks about the adult population here. But just in terms of the enrollment again, it was only 18 patients. So the larger percentage of patients are the younger. And so again, I think that's where we improve from here. I would anticipate that our Phase III population will not be limited to a requirement that it'd be a child with onset in terms of the benign tumor. And as you note, there is a distinct population of adults who develop this complication as well. Dr. Abuzzahab, could you provide some additional color?

Being a pediatric endocrinologist, I have to say, I think, sometimes when our kids grow up or graduate to the adult world, we do contact with them and they get more scattered. There are far more adult endocrinologists than pediatric endocrinologists. And I think sometimes that makes it a little bit harder to gather a larger population since this is a rare disorder. That being said, also for this particular Phase II study, I think one of the inclusion criteria was within 8 years of diagnosis where there was some limitation in candidate selection, [indiscernible] but maybe 6 years. So there was a limitation which you think skewed it to a little bit younger.

Yes, it's correct. And you raised a good point also that our investigators were concentrated in the pediatric endocrinology field. But Corinne, our goal will be not to limit it. I don't think from a biological standpoint, the unifying biology here is destruction of this pathway with destruction of the hypothalamus then the same biology should be a little bit independent of age is what we would expect.

Okay. And in the past, you've used kind of like a 3-month check in to see if patients are responding and then patients will stay on therapy if they are deemed responders or not. Do you expect that to be something you would employ in additional studies here in this population?

No. And here's the reason why. I think just to level set on that prior, so we use that strategy in our basket study, where we were trying to sort out the pathogenic -- likely pathogenic, if you will, mutations within this variant of unknown significance category. And so a 3-month trial becomes diagnostic in a sense in a world where it does not have a more specific way of identifying those patients. For our policy biallelics basically, we expect all of those patients [indiscernible] as one. So there's not that 3-month run-in period that's needed per se. For the BBS patient population with their clinical diagnosis, they have a full manifestation, again, with other organs being involved, which tells you that there is underlying pathogenic glass of function in the genetics that are there. This is a similar one. And maybe Dr. Abuzzahab, you could comment on the use of the growth curve in the diagnostic. Is this a difficult diagnosis to make?

It really is because the weight gain following surgery or radiation is just so remarkable if you could see it. There's really nothing else that does that.

So I think, Corinne, informal way of saying that I don't expect to use it 3 months. This was a 3-month trial, but again, there was no sorting, right? We didn't have a 30%, 50% response rate. We had -- literally all patients responded. Now 2 patients or 3 patients who have chosen not to continue are part of discontinuation, but they all had a biologic response.

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

Congrats on the data. Two from us. One for Dr. Abuzzahab. The first one is -- in terms of your experience with HO patients, is there a clinically -- is there a measurable or a clinically meaningful reduction in say, BMI and/or weight administration for -- greater than 5% high responder analysis. Is that considered clinically meaningful relative to other indications or could be whether or not they be genetically defined or not? And then I have a follow-up for the Rhythm team.

I mean, in this population, any decrease in BMI is clinically and significant. And the degree of weight loss, seeing in this, really reduces their risks for obesity-related conditions when they're older.

And for David and team, several of your setmelanotide programs that are ongoing, except for HO are in more genetically defined patient populations. Are there any other indications that are nongenetically defined or acquired. [indiscernible] that you think you could expand setmelanotide to use into with potentially larger patient populations?

Yes. I think, Joey, you raised an important point here and what I said in my opening comments there. What's really exciting about this one is we've got a therapy that's highly effective in a population of patients who have nothing. So for the HO world, again, this is potentially a transformative step for them. But it does provide further insights into this biology, and I commented about maybe helping us better understand the impact of the MC4 receptor outside the hypothalamus, number one. Number two, your specific question about other indications. I mean, there's very early research looking at antipsychotic medications where weight gain may be a complication of starting those medications and that's a world where -- so to say -- I mean, again, it's very early. It's not a priority risk for Rhythm at this point. But my -- the goal in sharing that objective and sharing that is simply to highlight to answer your question, yes, I think this could lead us to some additional areas over time.

[Operator Instructions] Our next question comes from Jeff Hung with Morgan Stanley.

The first is for Dr. Abuzzahab. Can you talk about the heterogeneity of HO patients you treat? And what other factors beyond weight loss might go into a patient's decision to be treated by a drug like setmelanotide?

I would say for most of my patients there who have varying degrees of other hormone deficiencies. Now, we think a little bit that MC4 is a hormone deficiency, I guess, in some ways. And so they are -- some of them have all pituitary hormones needing to be replaced and have only a few -- but the -- for many of my patients it's the weight gain and the changes in appetite and energy that are upsetting the most to them and to their families. And I think for them the chance to like be able to participate more in their family outings and specifically more with their families in addition to weight loss is a huge benefit to this medication.

Great. And then for management, you've talked about your confidence in showing efficacy in this population, but an outstanding question being the size of the safety database needed and you touched upon this. But can you clarify what is the uncertainty around that given that setmelanotide is already approved in multiple indications and has an established safety profile from past trials and patients on the drug?

Yes. No, Jeff, it's a good question. I don't know. I'm just saying this is -- as we know, in the regulatory world, there's always a question when you go into a new population, is there something specific about your drug in that population that you might not have seen in another population. So you get credit for your -- the work that's been done previously, but you still need to show safety and efficacy in your -- that new medication. Hopefully that answered the question? Next question?

[Operator Instructions] And I'm currently showing no further questions. I'd like to turn the call back over to David Meeker for closing remarks.

Okay. Great. Well, thanks all of you for tuning in for your questions and interest in what we see as incredibly exciting results. And as I said, I think, it's a big moment for the hypothalamic obesity population and it's certainly an incredibly important moment for Rhythm and with that we'll sign up. Talk to you soon. Bye.

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