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

[Presentation] Good day, and thank you for standing by. Welcome to the Rhythm Pharmaceuticals First Quarter 2025 Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to your speaker today, David Connolly, Investor Relations at Rhythm.

Thank you, Josh. I'm Dave Connolly here at Rhythm Pharmaceuticals. For those of you participating on the conference call, our slides can be accessed and controlled by going to the Investors section of our website, ir.rhythmtx.com. This morning, we issued our press release that provides our Q1 2025 financial results and a business update, and that press release is available on our website. Our agenda is listed on Slide 2. On the call today are David Meeker, our Chairman, Chief Executive Officer and President; Jennifer Lee, Executive Vice President, Head of North America; Hunter Smith, Chief Financial Officer; and Yann Mazabraud, Executive Vice President, Head of International is on the line and joining us from Europe. On Slide 3, I'll remind you that this call contains remarks concerning future expectations, plans and prospects, which constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed on our most recent annual or quarterly reports on file with the SEC. In addition, any forward-looking statements represent our views as of today and should not be relied upon as representing our views as of any subsequent dates. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to David Meeker, who will begin on Slide 5.

Thank you, Dave. So good morning, and thank you for joining. So we're about 1 month since our call highlighting the top line results from our Phase III trial in acquired hypothalamic obesity. We remain on track for a Q3 filing, including having an in-person Type B meeting scheduled with the FDA. I will say the FDA is responsive, and I would characterize our interactions as completely normal. We have reviewed all of the data, which we will present at upcoming meetings. The more we dig into the data, the more convinced we and I are that setmelanotide has the potential to transform the life of both the patient and their families. I will remind you of the top line data with a little additional color in the next few slides. Commercially, with BBS, we had a very good first quarter. In the U.S., demand as reflected in vials dispensed to patients continues to grow. The team, as Jennifer will describe, is making good progress on most fronts addressing the challenges of this complex disease. The growth in demand is obscured this quarter by the inventory shifts, which Hunter will walk you through. The international team continues to execute on its country-by-country BBS launch strategy and the HO contribution to revenues predominantly from France and Italy continues to grow, supporting our view of the unmet need and the level of interest in setmelanotide as. As we have highlighted, we're looking forward to the bivamelagon Phase II readout in Q3 and having something to say about the ongoing PWS study, Prader-Willi and the 718 weekly study in HO by the end of the year. And we remain well capitalized with a projected cash runway into 2027. On Slide 6, this is data from a publication by Professor Mller from Germany, a renowned expert in the field of hypothalamic obesity. It provides some numbers behind what we are learning as we get to know this community and review the data from this trial. The medical complexity and severity that these patients and their families are dealing with is unlike any disease I have worked on in my industry career. There are diseases with higher mortality rates, but very few with higher medical complexity. And you can see that from the numbers on the slide. 3.7 hospitalizations in the first 2 years after the injury, of which 23% required an ICU admission, 12 visits to their general practitioner and on average, 20 visits to a specialist. And even more strikingly, the average number of prescriptions written per month is 5.5. The average number of unique medications prescribed in the first 2 years is 22 and 89% of these patients require 3 or more therapies for neuroendocrine dysfunction. As the data from this trial shows us, including the exit interviews with patients and caregivers, the untreated hypothalamic obesity with its associated hyperphagia and fatigue represent a significant part of the medical burden they are dealing with. The fact that patients were willing to commit to this 52-week placebo-controlled trial given the incremental burden of testing and clinic visits, which are part of any trial, speaks to the motivation of this community to find solutions. We at Rhythm are highly motivated. On Slide 7, I'll provide you a little additional color around the results of the Phase III study. First, the top line and worth showing again with a 16.5% reduction in BMI in the setmelanotide cohort as opposed to a 3.3% increase in BMI in the placebo group for a placebo-adjusted difference of 19.8%. As we showed you last time, moving to Slide 8, there was no difference in effect between patients under 18 and those over 18, but we have broken this out further. So on Slide 9, we did stratify patients between 3 age groups, breaking out the under 18 to those between 12 and 18 and those less than 12. Adults may be a relatively homogeneous population, but there's a big difference between a 4-year-old and a 17-year-old. Here, you can see the 3 age cohorts and remarkably, they are similar again with placebo-adjusted BMI percent changes ranging from 19.2% to 21%. On Slide 10, A hallmark of the trials of setmelanotide in this disease has been the consistency of response. And as we showed you last call, 80% of the patients lost more than 5% suggesting some response. As always, the patients of greatest interest, at least to me, are the apparent nonresponders. And I gave 3 patient examples last call of patients who did not reach the 5% but had other data suggesting a response to drug. A more complete summary of that analysis is as follows: there were 17 out of 81 setmelanotide-treated patients who were not considered responders by virtue of reaching 5% or more in this analysis. 8 of these patients discontinued treatment prematurely and had their data imputed. Three of these 8 patients actually had reductions in BMI greater than equal to 5% at their last time point assessed, but were counted as nonresponders due to the conservative nature of the multiple imputation method, which uses the placebo patient data to generate the imputation values. Of the 9 nonresponders who did complete the trial, 6 of the 9 patients either had a response greater than 5% at some point during the trial and/or for the pediatric patients had a BMI Z score decrease greater than equal to 0.2, which is clinically significant. 2 of the 3 patients with no response and no other explanation had drug blood levels consistent with significant noncompliance. So in summary, the consistency we saw in the Phase II trial, the consistency of response we're seeing in the real-world French experience is evident here. This further analysis supports the thesis that the biology in this disease is driven by impaired signaling through the MC4R pathway with a consequent deficit in alpha melanocyte stimulating hormone. The consistency of the response to setmelanotide we see across this highly heterogeneous and medically complex patient population suggests we are helping to correct a fundamental biologic deficit. On Slide 11, I remind you of the disposition in this trial, the vast majority of the 143 patients enrolled, consisting of 120 in the pivotal cohort, 11 supplemental and 12 in the Japanese cohort have moved to the open-label extension trial. A total of 120 patients remain on treatment. That's 108 patients who transitioned to the open-label extension and the 12 Japanese patients who remain in the blinded portion of the study. And importantly, there were no new safety signals related to setmelanotide observed, which, of course, is in line with setmelanotide's well-established and well-understood safety profile. Consistent with prior experience, setmelanotide was also generally well tolerated in the study. And on Slide 12, which you've seen before, to remind you of the very significant opportunity in acquired HO. The unmet need is there. These patients are accessible. They're diagnosed and the setmelanotide data looks extremely promising. We believe we can make a significant difference in this disease. So with that, I'll turn the call over to Jennifer.

Thank you, David. Beginning on Slide 14, we are pleased to report that the demand for IMCIVREE as the only treatment that addresses the root cause of hyperphagia and obesity associated with Bardet-Biedl syndrome remains strong in the first quarter of 2025. Overall, we have seen continued increasing demand for IMCIVREE with a consistent number of new prescriptions received over the past several quarters, resulting in ongoing growth in patients on reimbursed therapy. During the first quarter, we did see an increase in the number of patients that transitioned to new insurance plans, which happens at the beginning of every year. This resulted in an increase in the number of patients that temporarily transitioned from receiving commercial drugs to receiving free drugs from our bridge program. I am pleased to report that we secured access for the vast majority of these patients and exited Q1 with the overall percentage of bridge patients back to normal levels experienced at the end of 2024. On the next slide, I will update you on 2 additional positive trends relating to improved Medicaid coverage and improvements in the breadth and depth of prescribers. Next slide. We continue to see increased breadth and depth of prescribers. In Q1, we saw the highest number of total prescribers within the quarter since the launch of IMCIVREE and saw a 13% growth in the total number of prescribers this quarter compared to Q4 of 2024. This growth was driven by an increase in new prescribers, which is an important driver of the business since launch to date, approximately 1/3 of new prescribers become repeat prescribers. This demonstrates that when a physician is educated to look for the clinical manifestations of BBS in their patients, they begin to find more BBS patients. Second positive trend is Medicaid access on the next slide. The last time we shared this metric was a year ago when the breakdown between states with positive coverage for IMCIVREE versus no coverage was approximately 85 to 15. We continue to work persistently to expand access. And in recent months, we have secured IMCIVREE-specific policies in 3 additional states. We now have IMCIVREE-specific policies or positive coverage decisions for IMCIVREE in states that account for greater than 95% of covered Medicaid lives, leaving less than 5% in states with no positive coverage for IMCIVREE to date. This success in securing access for IMCIVREE from Medicaid as well as commercial payers will serve as a strong foundation for our next potential launch in acquired hypothalamic obesity. We are excited by the potential to bring IMCIVREE to HO patients since our market research, both with physicians and patients and caregivers, points to a significant need for a therapy for this devastating disease. Next slide. We know endocrinologists remain critical for patients with hypothalamic obesity, enabling us to focus our efforts on this one specialty, which is the same specialty that accounts for about half of prescribers for BBS. Weight gain, lack of energy and hyperphagia were outlined by endos to have a significant negative impact on patients' day-to-day lives with current treatment options insufficient in addressing these symptoms for patients. As expressed by one endo, we need a treatment that is going to be more effective, well tolerated and safe to continue long term because this problem is not going to go away. These patients are going to be on this treatment for their lifetime. Once you withdraw the treatment, they will regain the weight and more. When shared a blinded target product profile, all physicians outlined they would prescribe setmelanotide for HO. On my next and my last slide, our research with patients and caregivers illustrates just how significant the impact of hunger and hyperphagia, decreased energy or fatigue and weight gain are for patients. As seen in the first quote, I was just feeling like a different person after the tumor and the hunger rules your life. These patients know what life was before the onset of these symptoms associated with HO, and they want their lives back. With that, let me hand it over to Yann.

Thank you, Jennifer. With IMCIVREE available through reimbursed access, named patient sales and our early access programs now in more than 15 countries outside the United States. We are seeing steady global growth in the number of patients on paid therapy and our global patients on treatment country by country. POMC and LEPR [indiscernible] patient population better identified in Europe than anywhere remain an important contributor in the international [indiscernible]. BBS, however, remains the main driver of revenue outside the United States with steady growth in reimbursed therapy. And Germany and France [indiscernible]. Also, more patients with hypothalamic obesity have access to IMCIVREE through early access programs and also name in -- of course, we are seeing growth with [indiscernible] both acquired and congenital hypothalamic obesity. But the early access program in generating growth we are now seeing in Spain and even where our first started therapy. Next slide. We are looking forward major European medical conference next week at which we have 10 presentations, including 5 orals. The first ever joint conference of the European Society of Endocrinology and the European [indiscernible] in Copenhagen. The 32nd European Congress on Obesity in Mlaga, Spain we are particularly looking forward to presentation of real-world data from the French program in hypothalamic obesity. Recall in the fall of 2024, French presented real-world data demonstrating the potential efficacy of setmelanotide in 8 patients with acquired hypothalamic obesity who achieved 12% BMI reduction at 3 months and 5 patients with greater than 21% BMI reduction at 3 months on setmelanotide. Next week, we will [indiscernible] acquired or congenital hypothalamic obesity. Also, there will be a presentation of German BBS which points as well as details on how our -- the genetic RAR in the DAYBREAK trial remain present PHIP. [indiscernible]

Yes. So Yann, you were breaking up a little bit here. So I think we lost some of your communication there. I'm just going to read briefly from your script just so everybody has the last part. I think I'll summarize briefly. Things are going incredibly well in Europe, as Yann highlighted. Hopefully, people got that and the BBS launch is progressing across countries. The ENDO SD meeting, which is coming up, and this is what he was speaking to at the end is we're excited about that, and we have multiple abstracts that are being presented there. And just to summarize what he said, make sure everybody heard it. So we previously presented data on the data from the initial 8 patients in the French real-world experience. And next week, we'll see data from 24 patients with acquired congenital obesity who have reached at least 3 months or more on setmelanotide. And then there will also be a presentation of real-world evidence of IMCIVREE for German BBS patients, which points -- will point to the benefit of reducing hyperphagia and obesity as well as details on how this specialized nursing support program contributes to patient and caregiver satisfaction. And then there'll be a publication or an abstract on the genetic rare MC4R pathway indication study in DAYBREAK, including presenting findings on patients with this PHIP variant, which is one of the variants which had particularly strong results in our initial Phase II DAYBREAK study, and we look forward to doing more work there. So that will be there. And I think I'll just comment that on the HO data, the 24 patients you're going to see, we're embargoed now, so we can't present that data, but you won't be surprised. There's nothing about that data set that's inconsistent with what we've seen so far. So with that, I'll turn it over to Hunter.

Thank you, David. Thank you, Yann. Rhythm had a very good first quarter. Let me walk you through the components on Slide 23. Revenue from global sales of IMCIVREE was $37.7 million in the first quarter of '25. The number of patients increased 14% globally during the quarter. The biggest driver of the Q4 to Q1 change in revenue was an inventory swing of $8.3 million at the specialty pharmacy that dispenses IMCIVREE to patients in the U.S. As we discussed in our Q4 call, the specialty pharmacy had purchased approximately $4.1 million more than it dispensed to patients in that quarter. This resulted in an increase in the specialty pharmacy's inventory to more than 22 days on hand, effectively pulling forward orders from Q1 into Q4. In the first quarter of 2025, this ordering and shipment pattern more than reversed itself. The specialty pharmacy ordered $4.2 million less than it dispensed to patients, reducing inventory days on hand to less than 9. Typically, the specialty pharmacy inventory runs between 10 and 15 days on hand. The value of IMCIVREE dispensed to patients in the U.S., the best measure of demand for IMCIVREE increased $1.1 million sequentially over Q4. Major drivers of this included a 4% price increase taken in January, an increase in the number of reimbursed BBS patients on therapy, an increase in the number of patients on bridge therapy at the start of the quarter, as Jennifer described earlier, that resolved itself by the end of the quarter and a modest decrease in patient compliance. Outside the United States, sequential revenue growth was strong at $3.1 million, primarily driven by France, Germany and Italy. Taken together, the $8.3 million inventory swing, the increase of $1.1 million in product dispensed to patients in the U.S. and the $3.1 million increase ex-U.S. resulted in a net revenue decrease of $4.1 million compared to the fourth quarter of 2024, reflecting timing difference from inventory shipment patterns in what was an otherwise strong period growth. Looking ahead, we don't expect such significant swings in IMCIVREE inventory at the specialty pharmacy as we experienced in the last 2 quarters. But if we do experience them, we will continue to highlight any significant impacts as we have in the past. Now I'll move to Slide 24 with our financial snapshot in Q1 2025. In comparison to Q1 2024, net product revenues increased $11.7 million or 45% over the first quarter of 2024. For some additional color on the P&L, gross to net for U.S. sales was 84.2%, generally in line with the 85% GTN we've reported in previous quarters. R&D expenses were $37 million for Q1 2025 compared to $128.7 million during the first quarter of last year when we incurred R&D costs of $92.4 million associated with the acquisition of bivamelagon from LG Chem. On a sequential basis, R&D expenses are down by approximately 10% from the $41.2 million we reported in the fourth quarter of '24 due to decreased spending on the pediatrics Phase III trial, DAYBREAK and EMANATE trials and decreased costs associated with the RM-718 Phase I trial. Also, we are seeing lower costs related to post-trial access due to a more efficient design for our open-label extensions. SG&A expenses were $39.1 million for the first quarter of 2025 as compared to $34.4 million for the first quarter of 2024. Sequentially, SG&A expenses increased modestly by less than 3% compared to Q4. For the first quarter of '25, the weighted average common shares outstanding were 63.1 million compared to 60.1 million for the first quarter of '24 and 61.6 million weighted average common shares outstanding in Q4. The increase quarter-over-quarter primarily reflect the approximately 1.3 million shares sold under the ATM program in December and January, which we announced in conjunction with our Q4 earnings. Cash used in operations was approximately $40.4 million compared to $19 million in the fourth quarter. This change represents an expected seasonal increase that occurs in the first quarter each year with the payment of annual bonuses company-wide. In addition, the $6.3 million cash consideration paid to reacquire the rights to IMCIVREE in China was recorded this quarter. Looking at cash flow going forward, the final going forward into Q2, just to remind everyone, the final $40 million portion of the license fee payable to LG as part of that bivamelagon transaction will be paid during the coming quarter. It was expensed in the first quarter of 2024, as previously mentioned. On Slide 25, we ended the quarter with $314.5 million in cash on hand, which we believe will be sufficient to cover all planned operations into 2027. As we touched on earlier, U.S. revenues were affected by an inventory swing from Q4 to Q1, which decreased the U.S. percentage of overall product revenue to 65% in Q1 from 74% in Q4. OpEx for Q1 2025 includes $2.9 million of stock-based compensation. We noted previously about reacquiring our rights in China for $6.3 million during Q1. This transaction was recorded as a reduction of license revenue of $5 million due to the termination of our licensing agreement with RareStone and a reduction of deferred revenue on our balance sheet of $1.3 million. Our GAAP EPS for the first quarter of 2025 was a net loss per basic and diluted share of $0.81. This includes $0.08 per share for the RareStone repayment and $0.02 per share from accrued dividends on convertible preferred stock of $1.3 million. Lastly, on Slide 26, our OpEx guidance remains unchanged. We anticipate approximately $285 million to $315 million in non-GAAP OpEx comprised of non-GAAP SG&A expenses of $135 million to $145 million and non-GAAP R&D expenses of $150 million to $170 million. With that, I'll turn the call back over to David for Q&A.

Thanks, Hunter. So in summary, again, hopefully, what you're hearing, Rhythm continues to grow by all metrics. I'll give you one additional metric. We're about 300 people now employed at Rhythm to manage the diverse set of activities we have going on. And as across everything, our commercial efforts, as you've heard, BBS launching progressively around the world, global expansion efforts and our development efforts, we're in a really good place. And I've been in this industry, again, as you all know, for a very long time, much of that time spent in clinical development. And I have to say, I don't know if I've had another Phase III set of data that has been more rewarding in terms of the fun you have analyzing that data set and realizing the impact that it is having and will have, hopefully, a much larger number of patients going forward. So we feel good about where we are. I look forward to your questions. And with that, we'll turn it over to Q&A.

[Operator Instructions] Our first question comes from Jon Wolleben with Citizens.

Congrats on the update. David, I hope you could talk a little bit more about those nonresponders you highlighted. It sounded like several of them are having good responses, but dropped out. So what were the reasons for those discontinuations?

Yes. I mean, again, there were a variety and they were across both placebo and treated. They mix from just patients withdrawing because they couldn't keep up with the clinical trial, either themselves or the family managing it. So that was about half of the group. And then the other, including some of the smaller in the placebo group were due to reactions. So GI, injection site overall, the patient who had the seizure disorder preexisting had uncontrolled seizures during the trial and ended up actually dying of uncontrolled seizures at the end of the trial. That patient did not complete. So that's the patient included in the dropout. I think as I've explained what I was trying to explain when patients drop out, their data does get imputed and the way companies are guided to handle that is in the most conservative way, which is not surprising, the FDA wants to make sure that they're not in any way getting to robust result here. So the imputation is done by using data from the placebo group in terms of their trajectory over the course of the trial, and that value is used to create or generate the imputation values. And obviously, the placebo patient group here gained weight. So if you're using data from that data set, it's going in the opposite direction of what might support evidence of an effect. So that's why I was just highlighting that 3 of the patients out of the 8 who dropped out had already reached a response at the point they dropped out, but the imputation took them down below that 5% level.

Can you talk just a minute about real-world persistence and understanding of expectations for adverse events and how that understanding keeps patients on drugs or not? Like what's the real-world experience? And how does that translate from the clinical data?

Yes. I mean we can talk to this more. I mean what we talked about generally across all of our patient populations treated on our commercial experience is we're globally with a number around 30%-ish of patients who discontinue. In the HO world, and we've gotten this question, are we going to see fewer discons there? And the number is still relatively small, but I think the answer is yes. I mean the discontinuation rate in this trial, again, was a little less than 10% of the total of 143 patients that were enrolled. Compliant, it looks like it was extremely high overall. And so part of my goal in giving you the background around the medical complexity is, yes, that's the world they're living in. But despite all of that, the importance of continuing setmelanotide and the relief they're getting from that, it seems to be incredibly high. So I think we're going to do better, maybe quite well in the HO population with regard to both discons and compliance.

Our next question comes from Derek Archila with Wells Fargo.

Congrats on the progress here. Just 2 quick ones from us. Just for Part C for RM-718, I know you highlighted enrollment will complete by the end of the year, but we just wanted to confirm whether you actually plan to share any efficacy data for patients reaching 16 weeks before the end of the year. And then the second question for Hunter. You noted some changes on compliance during the quarter. So I was wondering if you could just elaborate on that and I guess, how we should be thinking about that trending for the rest of the year?

I'll take the first one and then turn it over to Hunter. So yes, Part C is just getting underway. As you know, as I say, it's true, obviously, it's hard to guide until the trial is really up and running and you're enrolling at a more consistent rate here. So we're just at the beginning. The reason we're guiding to hopefully being able to say something by the end of the year is that we're not targeting necessarily a specific number of patients. So for example, for the bivamelagon trial, that's a blinded 4-arm trial, 28 patients. You got to enroll 28 and get them to the end. But in the open-label effort here for 718, it's also true for Prader-Willi. With the open label, we just want to get to a robust number, which is why my hope and expectation is that we will have enough patients treated for a long enough period of time that we will have something to say by the end of the year.

Derek, on compliance, we've generally seen compliance sort of in the low 80%, 80% ZIP code. And we had a very strong compliance rate in Q4, which was a bit of a tailwind in Q4, and it returned to a more normalized level in Q1.

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

I'm sorry if this was part of Yann's comments, I couldn't hear him clearly. But can you just talk to us about the importance of these continual data updates that you're expecting to make now at conferences going forward? It's our understanding from companies that we've spoken to or doctors that we've spoken to that they think that the data is pretty much perfect. So what additional data do you think is necessary?

Yann, it's right. I'll take that one. also, I'm not sure if your connection is back solid. Yes. No, it's a fair question, Tazeen. I think my view of particularly the rare disease world is every patient is incremental and news in a sense, particularly when you're early on. And so the French patient data that we presented last fall was it was only 8 patients, but it was incredibly important data, as I think we all realize because it highlighted a group that we hadn't studied in our Phase II, meaning these were all adults and with a mean age of 30, and they were also out about 11 years from the time of their insult. So it addressed based on small numbers, an important question there, which now this Phase III trial has also highlighted or answered, I think, which is it doesn't matter whether you're an adult pediatric patient, you're going to respond well. What is the value of now having a 24-patient update as opposed to 20. Again, it's just -- it's -- 24 is a lot more than 8. It's still a small number of patients. So it's not that we're going to have every quarter an update on how many patients are treated in France and Italy and some of these other countries, which you may have missed. I mean we do have individual patients sort of named patient settings and a few other countries as well treated for HO. So we'll do that for a little while, but not endlessly. So I don't know if that answers your question.

Yes. And then just on questions around seasonality. I just want to clarify, are you expecting to see any seasonality for the remaining quarters of the year?

Maybe, Jennifer, do you want to take that?

Yes. I think like overall, like Q1 is probably the biggest impact based off of what we outlined in terms of those insurance changes that happened just across the board for any patient population and the ability for us to work through with the new payer to regain insurance, that is what really hit us from a Q1 perspective. I think Q4, we don't have a real control in terms of what the specialty pharmacy orders. So that may be something that happens in the very last couple of quarters of the month in December. But beyond that, we haven't really experienced a lot of other seasonality throughout the year.

Just to add to that, if we look at our pattern of prescriptions written and approvals for reimbursement received, with the exception of the impact on change in the calendar year, we don't see a significant difference between the quarters.

Our next question comes from Phil Nadeau with TD Cowen.

Congrats on the progress. A few from us. First, David, you mentioned in your prepared remarks that you have an FDA meeting scheduled. Can you discuss what elements of the filing need to be ironed out with the FDA at this point? Any uncertainties? Or is the meeting more a formality?

It's -- I can just say probably for the past 5 years, I'm thrilled anytime we can get more meaningful interactions with the FDA, meaning just they're busy and have a lot to do. What I was excited about here is we got an in-person meeting, and this will be my first in-person meeting in about 5 years. So looking forward to that. In terms of why the meeting, yes, this is a -- you invariably have and they get called different things, but a meeting before a filing, and it is to clarify what we're presenting in the filing, how we look to present the data, make sure they're all aligned with how that's going to come through. So that's it.

Got it. Second question is on the Q4. Hunter, you noted that there was somewhat of an impact because of the time to get insurance reauthorizations and the bridging of patients on free drug. Could you quantify that impact in the quarter? Do you have a sense of how much revenue was hit by that in particular?

That was about a $700,000 effect.

Perfect. And then last question is on the payer mix. Can you remind us what the payer mix is for BBS between Medicare and Medicaid and private pay? And where do you expect that to go for the HO population?

Yes. So the commercial as well as the Medicaid population accounts for about like 80% with approximate equal split between the 2 with Medicare being a smaller portion in terms of impact of the BBS patient population, and we are currently still evaluating the HO opportunity to better understand what that payer mix looks like.

Our next question comes from Seamus Fernandez with Guggenheim Securities.

Great. So 2 really kind of focused in on the bivamelagon opportunity and how you see this advancing and the pace at which you can kind of bring that product forward should the Phase II program deliver the profile that you anticipate, which, again, if you could just remind us the profile that you're expecting. I recall, David, you saying that your hope for that product is that it would deliver efficacy comparable to what we've seen in HO with setmelanotide, but excluding the impacts of MCR1 and the hyperpigmentation. So that's my first question.

Yes. So you put the right emphasis on my hope. I'll see what the data shows. The way I'm now answering that question and these answers evolve a little bit, but they've evolved since I've seen the Phase III data. I think given the efficacy of setmelanotide, I shown in Phase III, the threshold here is really to be better than 10%. So I was what's clinically meaningful. That's certainly clinically meaningful. Does it have to be the same as what we saw with setmelanotide, meaning if we ended up short of the 16.5% without the placebo correction part, does that mean you don't have a drug? And I say no. I mean, I think you can have different formulations, oral versus subcu. Many patients might prefer an oral. I think the GLP-1 world is a good example of where everybody has got tied up in nuts about 2% or 3% differences in GLP-1 outcomes when clinically makes absolutely no difference at all. I mean they're all robust results, responses to that drug. So internally, I think our threshold would be -- we're looking for something north of 10%. I think if we get that, we have a drug. And then how quickly we can develop it, we are developing new formulations, which are going to be critical, most specifically for the pediatric population. We'll have both a liquid and a chewable tablet. So that's going to be a little bit gating in terms of getting forward. I can't put quite a time line on that. But what I will say is if we have positive data, we will move aggressively to get into a Phase III effort, specifically in HO. And in parallel, we'll look at our strategies for doing BBS and POMC, but we will certainly move quickly to get into HO. And maybe we have to stagger a little bit in terms of how peds come into that depending on availability of product.

Great. And a follow-up to kind of pipeline opportunity and questions there. In the PWS opportunity, can you talk a little bit more about how you see that opportunity potentially emerging for MC4R specifically targeted agents, largely because we know that the first effort kind of missed the mark, but I know you're testing higher doses. So just trying to get a better sense of the PWS opportunity that you see for the product and if there are additional learnings that have kind of brought you forward to the willingness to kind of pursue a higher dose here.

Yes. So let me just remind you a bit on the original study. So yes, I think we used too low a dose, but it wasn't just dosing in that first trial. It was too short a trial, and it was a complicated design with crossover and the like. So as we've said and I've said, I don't think we learned much, if anything, from that original effort, one. Two, I think we maybe have some increased level of confidence in the biology here. I mean the -- this pathway is absolutely part of what is impaired in patients with Prader-Willi. Now that's a very complex disease. There's a lot of other things going on, other genes which are deleted and maybe impacting things like behavior and the like, which makes it more challenging to study. So with the context that this is a tough disease, and I've always thought you could have a drug which works and maybe your trial fails just because the disease in the background is so challenging. That said, yes, I put our sort of general probability of success here, which is kind of a non-answer, sort of the 50-50 range, but it's a legitimate 50-50. And I have to say -- so what are we looking for? The bar is lower in Prader-Willi. So I think HO, we came in and we had the Phase II data, we're looking for something north of 10. We got ended up with 16, placebo adjusted of almost 20. That's not what we're looking for in Prader-Willi. Prader-Willi, nothing helps those patients lose weight. [indiscernible] drug just got approved for decreasing their hunger. But there's a big unmet medical need, which remains there. So anything that moves the needle there, that's going to be interesting and something I think we'll seriously look to take forward.

Our next question comes from Whitney Ijem with Canaccord Genuity.

Just wanted to follow up on HO and kind of the launch trajectory versus BBS. I know you've talked a lot about the specifics of the HO patient population that should lead -- that hopefully will lead to kind of faster uptake or a different launch trajectory. I think most of those comments have been thinking about the U.S. or contemplating the U.S., but it seems those same things should be the case in Europe with potential for maybe even more momentum just given some of the early asset progress that's been made in the HO front there. So just curious if you can talk a little bit more about how to think about HO uptake in Europe specifically relative to what we've seen in BBS so far.

Yes. Yann, do you want to give it another shot, and we'll just see how you're connection is. If not, I'll take it back.

Yes. I try as I said the engagement with the is very...

Yann, Yann, Yann? I'm going to stop here just because you're losing too much of what you said there. So I'll give you my answer, Whitney. There's a lot of things about Europe, rare diseases in general, HO specifically, which are, of course, advantageous from a launch standpoint and the centers of excellence aspect of this, patients tend to be more concentrated. That said, I think the dynamic in Europe, which is going to be similar to the U.S. is heavily concentrated in the endocrinologists. These patients, they have a very high percentage of them have pituitary insufficiency, and they are chronically managed by endocrinologists. And so to that extent, it will be very similar between the U.S. and Europe in terms of our approach to that market. And then the rate at which they come on, I don't know if it's going to be different. I mean they have different reasons for why it may go faster or slower either in the U.S. or Europe. And I think what we've seen, BBS, for example, has not been so different. And I think that may be the case here. I do think, as we've said and we'll continue to say, HO is a very different opportunity than BBS. So some of that will be reflected in our launch trajectory, of course.

Got it. That's helpful. And then thinking about the label, can you just remind us how you are thinking about that currently? I know I think we're expecting an acquired HO-specific label, but are -- should we be thinking about BMI requirements or age or time from injury, any other kind of parameters that we should be thinking about?

So I don't know. We have had 0 interaction around label to date, so I don't have any insight there. In general, FDA labels your drug based on how your inclusion/exclusion criteria are written in the trial. The BMI criteria, FDA is moving away from that. So I'm actually not expecting that to be part of it. I mean this threshold of 30 being a magical number, whereby above and below it, you're obese or not obese. So I don't expect, hopefully that, that will not be a bit because it's not helpful. And the other thing for HO, which I think they will understand, this is about the change in trajectory. It's not about an absolute level of weight or BMI. It's about you were at a level of "relative" normality before you had your injury or your insult and then following the injury, then you have a rapid acceleration of your weight gain and increasing your BMI. So long story short, I don't think it's going to be there. Age-wise, we went down to 4. We've gone down to -- we're approved for 2 and above for BBS and POMC. I think this trial only studied 4, so 4 and above, and we had a 4 year-old in the trial. So I would expect minimally we'll get a 4 and above in terms of age. So not really an age restriction on what we're seeing here. And then we have hunger in the label in Europe. We have tried to get it in here that we have the ability to promote. We have data on hunger in the label. We'd like to get it in the indication statement. To me, that's been more about our inclusion and exclusion criteria. It's a key secondary in this trial. We hit hunger, we're going to go back and try again. And I think that's -- it's an important part of the indication statement. So we'll work hard to get it, but to be seen.

Our next question comes from Dennis Ding with Jefferies.

Just one for me. So consensus has HO revenue ramping from around $55 million, $60 million in 2026 to $1 billion plus in 2030. So there's quite a steep ramp in just 4 to 5 years of launch. Can you talk about your level of confidence that the launch will be solid? And what are the different moving parts that could drive revenue higher or lower than consensus?

Yes, Dennis, thanks. So I think consensus and ourselves, we're all continuing to work a problem none of us, of course, know exactly. So I'm not going to guide on the revenue piece of it specifically. I'll reinforce some of the elements to try to answer the other parts of your question. Fundamentally different. And I've talked before, the numbers here, 5,000 to 10,000 in the U.S., similar numbers in Europe, aren't arguably that much larger than BBS, right, 4,000 to 5,000 in BBS. But of that 5,000 to 10,000, a much, much higher percentage of those patients are diagnosed. They're visible. They have complex and they're actively being managed by specialists, and that specialist is endocrinologists. And about 50% of the patients -- of the writers -- script writers in the U.S. for BBS happen to be endocrinologists. So this is a world we're in. HO will be even more concentrated in the endocrinology world and as Jennifer and her team continue to work to develop the plans for launch, we will approach this in a different way than we did with BBS. In a rare disease world where the majority of patients are not diagnosed, you're trying to build a system that helps them get to a diagnosis. You don't find the patients by knocking on doors. You really find it by working with a system and then a patient gets to the diagnosis, then often they find us, some of them, we find them. In this, which is much more specialty like if they're concentrated in a specialty, you can cover that specialty. And our goal will be in a tiered way to cover certainly those endocrinologists, which is a significant number where the majority of these patients sit. So all of that says it should be a different ramp than we're seeing with BBS. Now that said, it's still a $375,000 a year price point. There'll be no change in price. That puts a natural drag on any launch, you have a prior authorization as you go through. And so there'll be a balance between some of this. We have a huge advantage of having been out there around BBS. It's not like we're new to this community. They know us. Increasingly, people know the drug. And increasingly, people are seeing the importance of MC4R pathway as this is a critical fundamental underlying biology. So all of that -- how that nets out, I don't know, but I'll summarize and leave it with. Yes, it's going to be a trajectory. I can't comment on whether that -- those numbers and consensus are going to be the ones we're going to hit.

Our next question comes from Leland Gershell with Oppenheimer.

Great to see the consistency across the age subgroups in the HO study. A couple of questions from us. First, a question for Hunter. Apologies if I missed it in the discussion about inventories. But should we expect lumpiness this year as we model quarterly revenue? Should we think about another fourth quarter kind of inventory stocking? And then also a question for Jennifer. Just on your comments about the 1/3 of first-time prescribers turning to repeat prescribers. Is that principally limited by simply the number of patients who fall under indication? Or are there factors maybe limiting the prescribers -- repeat prescribers?

So on the lumpiness, there are factors that are a normal pattern, that do tend to do a little bit of stocking during the fourth quarter. It's a way they try to manage their -- we believe it's a way they try to manage their gross margins because they think there may be price increases coming in the new year. It's not isolated to Rhythm. Obviously, it's a very common factor across the industry. Some of the lumpiness occurs by things as arcane as the fact that the quarter ended on a Monday, which is the day -- Monday, 31st of March, which is the day when SPs usually place their order, but they don't receive it until the next day. So that type of thing, if you would like to try and forecast that level of minutia, I wish you luck. I can't do it. But again, overall, we don't think the moves in days on hand are going to be this significant. We think, in general, they will sit in sort of the 10- to 15-day range on average. And the rest around that will just be the vagaries of timing and to some extent, ways they may try to manage their own gross margin.

And to the other question just regarding the repeat prescribers. I think in disease like BBS and if I compare BBS to HO and what a follow-on to what David has been outlining. I think for an indication like BBS, we sort of have smaller little breadcrumbs where the teams are really scouring to get to a physician who may have this type of patient population and educating them so that they are aware so that when that patient comes to them, they are able to get that patient to a diagnosis. For HO in contrast, I think the breadcrumbs are much larger that will lead us to the right physician more quickly in terms of being able to educate and engage the physician population. Once a physician actually gets a patient to a diagnosis, then they realize that this is something that they should be aware of as this patient with all these different symptoms comes to them. And it just becomes more of a piece of these patients could be anywhere. And sometimes they go to a physician who has already had experience with a BBS patient. And other times, they're in the hands of someone who -- that is the first patient diagnosed. I will say that once that physician diagnoses and has a great experience on IMCIVREE, then they are more likely to also prescribe this drug for those particular patient populations. So it's a bit of a mix of that in terms of where the patients land in terms of care and also the positive experience after touching and seeing what IMCIVREE can do for the BBS population that results in a repeat prescriber.

And so, just to reinforce again what Jennifer said that, why don't the 1/3 patients all prescribe another drug as a rule, as she said, if you get 1 patient on, you have that experience, you're a believer, then it's more a question of do you have other patients.

Our next question comes from Michael Ulz with Morgan Stanley.

This is Selina on for Mike. For the congenital HO substudy, could you describe the patient mix that you're seeing among the different pituitary deficiency disorders included? And any learnings on reliably diagnosing congenital HO?

Yeah, I know we're, I don't know, way too early to answer that in any kind of meaningful way. I mean, I think the list we've talked about of, you know, SOD, septo-optic dysplasia, pituitary stalk interruption syndrome, multiple pituitary deficiency, I mean, we're going to see all of those. Right now, I would say the SOD pituitary stalk interruption, may be 2 of the more common, but we're so early, I just can't answer that in a meaningful way about how it will break out across the different, "categories."

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

For the IMCIVREE launch of BBS, can you disclose the number of written TRx and reimbursed TRx in the U.S. in the first quarter?

Yeah, we're not breaking those out, Joey. I mean, we did in the beginning, just to give everybody a sense, because we didn't have revenues that spoke meaningfully to where we are. I think now we're very much relying on the revenues, which are a more holistic view of how the market's doing. That's right. So, we gave you color around it, but we're not going to break out the exact numbers.

[Operator Instructions] Our next question comes from Raghuram Selvaraju with H.C. Wainwright.

Firstly, I was wondering if you could comment on any qualitative differences that you expect to see and implement in the context of the commercial rollout in hypothalamic obesity relative to the other indications in severity as already approved. And I'm just trying to look here for any changes in broader marketing and promotional strategies that you might utilize in this specific indication.

I think there are similar aspects in terms of any rare disease where the trajectory is really based off of how quickly you can identify the patients, because usually, and is the case here, for both BBS and HO, there was a need for an additional therapy. We have done research, we've gathered feedback from our field team who have started engaging with physicians just around better understanding the HO market. The pieces that, you know, make us feel very positive about the opportunity is that consistently the comments expressed about the unmet need in this particular population is so incredibly high. We hear that from patients and caregivers as well, as I outlined, just in terms of our blinded TPP, which we went out with slightly less efficacy than what we actually saw from a top-line data perspective. The reaction to IMCIVREE's efficacy as well as overall profile has been very overwhelming in terms of positive feedback from the physician population, so those 2 pieces are, you know, sort of rife in terms of the need that exists. And the other comment that David had outlined, for HO, these patients, because of all of the other clinical manifestations due to what they went through from a treatment perspective, they are in the hands of these endocrinologists, you know, the vast majority of them, like it could be 80% of them are still seeing endocrinologists, so that specialty call and that ability to go to that particular physician's lab with data that we have to be able to hone us down to which of those, even within this specialty, is much higher than, like I said, the breadcrumbs that we started with in BBS where there was no ICD-10 code, they are scattered amongst various different physicians. So I think those dynamics make it a more interesting and exciting potential launch for us.

Great. And then secondly, very quickly, in the week of the RareStone termination, I was just wondering in the context of the broader international strategy, how you intend to go forward in China if you are looking at the possibility of bringing in a replacement partner, or if your assessment of the China commercial opportunity, you know, has kind of signaled an evolution in your thinking about how best to penetrate that opportunity.

Yes, no, thanks. So we're thrilled to have that, you know, the rights to China back, I just feel good about having global rights here, number 1. Number 2, we absolutely are expanding globally, I'm really excited about the Japan opportunity, we haven't talked about that on this fall, but that's going to be a very meaningful opportunity in HO. China itself, we learned a lot in our partnership with the RareStone, and it was incredibly helpful in that sense in that, you know, they did some good work, other work had been done. The genetic side of this opportunity is probably less in China, not that it's not there, but HO is absolutely there, and I don't have numbers for you today, but we know it's there. So we will have a China strategy today, I wouldn't say we're committed to any particular course of action, meaning, you know, would we go alone, which I think is, we can go alone in Japan, much more challenging perhaps to go alone in China, so that would suggest we'd need a partner, but all that's to come. But I think, you know, China and Asia, you know, in a larger sense, Taiwan, South Korea those are meaningful opportunities, and we'll work our way through that and, you know, keep thinking about what's the right strategy for China.

Our next question comes from Paul Matteis with Stifel.

Sorry about that, I think I saw this here earlier, appreciate you fitting me in. Just going back to biz and all of that really quickly, anything you guys can say about safety from the study, given that it's pretty far along now, anything just on the idiosyncratic safety side related to liver or anything else that kind of you're saying that would give you more comfort in the molecule? And then I just wanted to clarify, David, on the bar, I mean, 10% makes sense, but this study is meaningfully shorter than the setmelanotide phase III, so how do you think about the bar for the shorter phase II? Thanks.

So on the safety side, I guess, you know, it's blinded, but obviously you follow the safety in a blinded sense, and all I will say, there's no significant safety signals here that we're concerned about, you know, I don't have fine detail in terms of looking at individual patients' LFT data, but if there was a serious adverse event related to LFTs, we would see that. So we're not seeing any of that. So I would categorize our blinded view of all that you're assuring, number 1. And then 2, your question on the bar, it's a good one, which I always don't like being boxed in, you know, particularly around data. There's always context around data, and particularly in a disease, I mean, the means are, I'm not at all interested in the mean value so much. I'm very much interested in paying my patient, and you know, if the mean doesn't get to 10%, but you can explain the couple of patients that were dragging the mean down, then okay, you've still got a drug. So we'll look at the data that way. You know, one way of looking at this is our phase 2 data, if you remember, with setmelanotide was 16 weeks, and you know, they did hit, you know, almost all of those patients had 10% or greater, or were on track to lose 3% or greater. So I think 10% is not an unreasonable target here, in terms of using setmelanotide as the bar, but there'll be context that we'll have to take into consideration. And it 16 weeks is relatively short.

Thank you. I would now like to turn the call back over to David Meeker for any closing remarks.

Okay. Well, thanks, everybody. A long call this morning, a lot of questions. I appreciate that, and we look forward to our next update.

Thank you. This concludes the conference. Thank you for your participation. You may now disconnect.