Rhythm Pharmaceuticals, Inc. (NASDAQ:RYTM) Q1 2025 Earnings Call Transcript

Rhythm Pharmaceuticals, Inc. (NASDAQ:RYTM) Q1 2025 Earnings Call Transcript May 7, 2025

Rhythm Pharmaceuticals, Inc. misses on earnings expectations. Reported EPS is $-0.81 EPS, expectations were $-0.69.

Operator: Good day, and thank you for standing by. Welcome to the Rhythm Pharmaceuticals First Quarter 2025 Earnings Conference Call. At this time, all participants are in a listen-only mode. Please be advised that today’s conference is being recorded. After the speakers’ presentation, there will be a question-and-answer session. [Operator instructions]. I would like to hand the conference over to your speaker today, David Connolly, Investor Relations at Rhythm.

David Connolly: 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 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.

David Meeker: Thank you, Dave. So, good morning and thank you for joining. So, we’re about one month since our call highlighting the top-line results from our Phase 3 trial on acquired hypothalamic obesity. We remain on track for a Q3 filing, including having an in-person Type D meeting scheduled with the FDA. I’ll 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’ll 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 US, demand as reflected in vials dispensed to patients, continues to grow. The team, as Jennifer will describe, is making good progress on multiple 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 (indiscernible). As we have highlighted, we’re looking forward to the bivamelagon Phase 2 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 Müller 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 two 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 two years is 22, and 89% of these patients require three 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’re 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 to not let them down.

On Slide 7, I’ll now provide you a little additional color around the results of the Phase 3 study versus the top-line. And as we’re showing again, with the 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 three 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 four-year-old and a 17-year-old. Here you can see the three age cohorts, and remarkably they’re 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 non-responders. And I gave three 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. Eight of these patients discontinued treatment prematurely and had their data imputed. Three of these eight patients actually had reductions in BMI greater than equal to 5% at their last time point assessed, but were counted as non-responders due to the conservative nature of the multiple imputation method, which uses the placebo patient data to generate the imputation values.

Of the nine non-responders who did complete the trial, six of the nine 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. Two of the three patients with no response and no other explanation had drug blood levels consistent with significant non-compliance. So, in summary, the consistency we saw in the Phase 2 trial and the consistency 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’ll 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 is 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.

Jennifer Lee: 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 transition 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 drug to receiving free drug from our Bridge program.

I’m 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’ll update you on two additional positive trends relating to improved Medicaid coverage and improvements in the breadth and depths of prescribers. Next slide. We continue to see increased breadth and depths 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 a third 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 from IMCIVREE versus no coverage was approximately 85 to 15. We’ll continue to work persistently to expand access, and in recent months we have secured IMCIVREE-specific policies in three 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 endocrine neurologists 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.

Yann Mazabraud: Thank you, Jennifer. We available to reimburse access name patient cells or 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 (indiscernible) global (indiscernible) patients on treatment country by country. (Indiscernible) the patient population that’s better identified in Europe than anywhere (indiscernible), remain an important contributor in the international (indiscernible). BBS, however, (indiscernible) the main driver of revenue outside United States, with steady growth in patients (indiscernible) therapy. In Germany and France (indiscernible). Also, more patients with hypothalamic obesity are (indiscernible) access to (indiscernible) through early access programs and also (indiscernible).

Of course, we are (indiscernible) with paid (indiscernible) both acquired and congenital hypothalamic obesity, but the early access for our (indiscernible) growth we are now seeing (indiscernible) in Spain and even (indiscernible) where our first (indiscernible) has started therapy. Next slide. We are looking forward (indiscernible) major European medical (indiscernible), including (indiscernible) the European (indiscernible) technology, and the European (indiscernible). The 32nd (indiscernible) in Madagascar. We are particularly looking forward to present (indiscernible) of real-world data from the French (indiscernible) people having hypothalamic obesity. Recall in the fall of 2024, France (indiscernible) presented real-world data demonstrating the potential efficacy of setmelanotide in eight patients with acquired hypothalamic obesity who achieved 12-point (indiscernible) patients with greater than 21 (indiscernible).

Next week, we’ll (indiscernible) with acquired or congenital hypothalamic obesity (indiscernible) reach (indiscernible). Also, there will be a presentation of (indiscernible) for German BBS (indiscernible), which points (indiscernible), as well as details on how (indiscernible) contribute (indiscernible) in the Daybreak trial (indiscernible) patients (indiscernible). Altogether, we have 10 presentations at these two conferences, plus two symposia for (indiscernible) this level of activity (indiscernible) level of support and the very strong interest (indiscernible).

David Meeker: 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 SP 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, I want to make sure everybody heard it. So, we previously presented data on the – data from the initial eight patients in the French real-world experience.

Next week, we’ll see data from 24 patients with acquired or congenital obesity who have reached at least three months or more in setmelanotide. And then there’ll also be a presentation of real-world evidence of IMCIVREE for German BBS patients, which 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 studied in Daybreak, including we’re presenting findings on patients with this PHIP variant, which is one of the variants which have particularly strong results in our initial Phase 2 Daybreak study. And we look forward to doing more work there.

So, that’ll 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.

Hunter Smith: 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 2025. The number of patients on reimbursed therapy 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 US. 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 nine. Typically, the specialty pharmacy inventory runs between 10 and 15 days on hand. The value of IMCIVREE dispensed to patients in the US, 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 US, and the $3.1 million increase ex-US, 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 of growth. Looking ahead, we don’t expect such significant swings in IMCIVREE inventory at the specialty pharmacy as we experienced in the last two quarters, but if we do experience them, we will continue to highlight any significant impacts, as we have done in the past.

Now, I’ll move to Slide 24 with our financial snapshot from 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 US sales was 84.2%, generally in line with the 85% GTM 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 2024 due to decreased spending on the pediatrics Phase 3 trial, Daybreak and Emanate trials, and decreased costs associated with the RM-718 Phase 1 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 2025, the weighted average common shares outstanding were 63.1 million, compared to 60.1 million for the first quarter of 2024, and 61.6 million weighted average common shares outstanding in Q4. The increase quarter-over-quarter primarily reflects 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 companywide. 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 – and going forward into Q2, just to remind everyone, the final $40 million portion of the license fee payable to LG as part of the 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, US revenues were affected by an inventory swing from Q4 to Q1, which decreased the US percentage of overall product revenue to 65% in Q1 from 74% in Q4.

OpEx for Q1 2025 includes $12.9 million in 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.

David Meeker: Thanks, Hunter. So, in summary, again, hopefully what you’re hearing, Rhythm continues to grow and 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 I look across everything, our commercial efforts, as you’ve heard, BBS launching progressively around the world, our global expansion efforts, and then 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 3 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 for a much larger number of patients going forward.

So, we feel good about where we are. Look forward to your questions, and with that, we’ll turn it over to Q&A.

Q&A Session

Operator: [Operator instructions]. Our first question comes from Jon Wolleben with Citizens. You may Proceed.

Jon Wolleben: Hey, thanks for taking the question and congrats on the update. David, I hope you can talk a little bit more about those non-responders you highlighted. It sounded like several of them were having good responses, but dropped out. So, what were the reasons for those discontinuations?

David Meeker: Yes, I mean, again, there were a variety and they were across both placebo and treated. They mixed 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 in the – small number 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 a patient who was included in the dropout. I think as I’ve explained – what I was trying to explain with, when patients drop out, their data does get imputed and the way companies are guided to handle that is done in the most conservative way, which is not surprising.

The FDA wants to make sure that they’re not in any way getting to a 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 the – 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 three of the patients out of the eight who dropped out had already reached a point of response at the point they dropped out, but the imputation then took them down below that 5% level.

Jon Wolleben: And 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?

David Meeker: Yes, I mean, we can talk this more. I mean, what we’ve talked about generally across all of our patient populations treated, our commercial experiences, 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 discontinuations there? And the number’s 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% off the total 143 patients that were enrolled. Compliance 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 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 discontinuations and compliance.

Jon Wolleben: That’s helpful. Thanks for the color.

Operator: Thank you. Our next question comes from Derek Archila with Wells Fargo. You may proceed.

Derek Archila: Hey, good morning, and thanks for taking the questions. Congrats on the progress here. Just two 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. Thanks.

David Meeker: Yes, I’ll take the first one and then turn it over to Hunter. So, yes, Part C is just getting underway. As you know, it’s as we say, and 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, so we’re not targeting necessarily a specific number of patients. So, for example, for the bivamelagon trial, that’s a blinded forearm trial, 28 patients. You’ve 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.

Hunter Smith: And Derek, on compliance, we generally have 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.

Derek Archila: Understood. Okay. Thank you.

Operator: Thank you. Our next question comes from Tazeen Ahmad with Bank of America. You may proceed.

Tazeen Ahmad: Hi, good morning. Thanks for taking my question. 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?

David Meeker: Yann, if it’s all right, I’ll take that one. Also, I’m not sure if your connection’s 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. So, the French patient data that we presented last fall was – it was only eight patients, but it was incredibly important data. I think we all realized because it highlighted a group that we hadn’t studied in our Phase 2, 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 insert. So, it addressed, based on small numbers, an important question there, which now this Phase 3 trial has also highlighted or answered, I think, which is, it doesn’t matter whether you’re an adult or pediatric patient, you’re going to respond well.

What is the value of now having a 24-patient update as opposed to an eight? Again, it’s just – 24 is a lot more than eight. 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 name patient settings in 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.

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

David Meeker: Maybe, Jennifer, you want to take that one?

Jennifer Lee: 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 orders of the month in December. But beyond that, we haven’t really experienced a lot of other seasonality throughout the year.

Hunter Smith: Yes, 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.

Tazeen Ahmad: Okay. Thank you.

Operator: Our next question comes from Phil Nadeau with TD Cowen. You may proceed.

Phil Nadeau: Good morning. Congrats on progress and thanks for taking our questions. 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?

David Meeker: I can just say probably for the past five 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 five 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.

Phil Nadeau: 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 – for drug. Could you quantify that impact in the quarter? Do you have a sense of how much revenue was hit by that in particular?

Hunter Smith: That was about a $700,000 impact.

Phil Nadeau: 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?

Jennifer Lee: Yes, so the commercial as well as the Medicaid population accounts for about like 80%, with approximate equal split between the two, 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.

Phil Nadeau: Great. Thanks for taking our questions.

Operator: Thank you. Our next question comes from Seamus Fernandez with Guggenheim Securities. You may proceed.

Seamus Fernandez: Great. Thanks for the question. So, two 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 2 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.

David Meeker: Yes, so you put the right emphasis on my hope. We’ll see what the data shows. The way of now answering that question, and these answers evolve a little bit, but they’ve evolved since I’ve seen the Phase 3 data, I think given the efficacy of setmelanotide, I said shown in Phase 3, the threshold here is really to be better than 10%. So, 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? I say no. I mean, I think you can have different formulations, oral versus a subq. Many patients might prefer an oral. I think the GLP-1 world is a good example of where everybody’s getting tied up in nuts about 2% or 3% differences in GLP-1 outcomes when clinically it makes absolutely no difference at all.

I mean, they’re all robust results or 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 a quite a timeline on that, but what I will say is if we have positive data, we will move aggressively to get into a Phase 3 effort specifically in HO, and in parallel, we’ll look at our strategies for doing BBS in Pam C. But we will certainly move quickly to get into HO, and maybe we have to stagger it a little bit in terms of how peds come into that, depending on availability of product.

Seamus Fernandez: Great. And a follow up to kind of pipeline opportunity and questions there, 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. Thanks.

David Meeker: 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, number one., two, I think we maybe have some increased level of confidence in the biology here. I mean, 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’ve 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 2 data. We’re looking for something north of 10. We 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. Soleno’s 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.

Seamus Fernandez: Great. Thanks so much.

Operator: Our next question comes from Whitney Ijem with Canaccord Genuity. You may proceed.

Whitney Ijem: Hey, you all. Thanks for taking the question. 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 US or contemplating the US, 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 access progress that’s been made on 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.

David Meeker: Yep. Yann, you want to give it another shot and we’ll just see how your connection is? If not, I’ll, I’ll take it back.

Yann Mazabraud: Yes, I will try. So, the first (indiscernible) as I’ve said (indiscernible) is the engagement with the (indiscernible) and it is very (indiscernible).

David Meeker: Hey, Yann, I’m going to stop you just because we’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 that the centers of excellence aspect of these patients tend to be more concentrated. That said, I think the dynamic in Europe, which is going to be similar to the US, is heavily concentrated in the endocrinologists. These patients, they have – a very high percentage of them have pituitary insufficiency, and they’re chronically managed by endocrinologists. And so, to that extent, it’ll be very similar between the US 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 US or Europe. And I think what we’ve seen, BBS for example it’s 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.

Whitney Ijem: 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 should we be thinking about BMI requirements or age or time from injury? Any other kind of parameters that we should be thinking about?

David Meeker: So, don’t know. We have had zero 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, meaning 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 increasing your BMI.

So, long story short, I don’t think it’s going to be there. Age-wise, we went down to four. We’ve gone down to – we’re approved for two and above for BBS and Pam C. I think we – this trial only studied four, so four and above, and we had a 4-year-old in the trial. So, I would expect minimally we’ll get a four 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-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 it’s an important part of the indication statement. So, we’ll work hard to get it, but to be seen.

Whitney Ijem: Awesome. Thanks so much.

Operator: Great. Thank you. Our next question comes from Dennis Ding with Jefferies. You may proceed.

Dennis Ding: Hi, good morning. Thanks for taking the question. 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 four to five 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? Thank you.

David Meeker: 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 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 US, 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 script writers in the US 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 being – 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 different trajectory. I can’t comment on whether those numbers and consensus are going to be the ones we’re going to hit.

Dennis Ding: Great. Thanks for the color.

Operator: Thank you. Our next question comes from Leland Gershell with Oppenheimer. You may proceed.

Leland Gershell: Hi, good morning. Great to see the consistency across the age subgroups in the HO study. A couple of questions from us. First question for Hunter, apologies if I missed it in the discussion about in 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 also, question for Jennifer, just on your comment about the, about a third of first-time prescribers turning into repeat prescribers. Is that particularly limited by simply the number of patients who fall under IMCIVREE’s indications, or are there other factors that may be limiting the prescribers becoming repeat prescribers? Thank you.

Hunter Smith: So, on the lumpiness, there are factors that are a normal pattern. You know SPs 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, the 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 minutiae, 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’ll just be the vagaries of timing, and to some extent, ways they may try to manage their own gross margin.

Jennifer Lee: And to the other question just regarding the repeat prescribers, I think in a disease like BBS, and if I compare BBS to HO and what – 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’re 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 with that 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 diagnosis and has a great experience on IMCIVREE, then they’re 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.

David Meeker: And so, Leland, just to reinforce again what Jennifer said, that why don’t the one-third of patients all prescribe another drug as a rule? As she said, if you get one patient on, you have that experience, you’re a believer, then it’s more a question of do you have other patients?

Leland Gershell: That’s very helpful. Thanks very much.

Operator: Thank you. Our next question comes from Michael Ulz with Morgan Stanley. You may proceed.

Selena Zhang: Hello, this is Selena on from Mike. Thanks for taking our question. For the congenital HO sub-study, 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. Thank you.

David Meeker: Yes, no, 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 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 stock maybe interruption, maybe two the more common, but we’re so early, I just can’t answer that in a meaningful way about how it’ll break out across the different “categories.”

Operator: Thank you. Our next question comes from Joseph Stringer with Needham & Company. You may proceed.

Joseph Stringer: Hi. thanks for taking our questions for the IMCIVREE launch in BBS, can you disclose the number of written TRX and reimbursed TRX in the US in the first quarter?

David Meeker: Yes, we’re not breaking those out, Joseph. 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 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.

Joseph Stringer: Okay. Thank you.

Operator: Thank you. [Operator instructions]. Our next question comes from Ram Selvaraju with H.C. Wainwright. You may proceed.

Ram Selvaraju: Thanks very much for taking our questions. 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 for which IMCIVREE is already approved. I’m just trying to look here for any changes in broader marketing and promotional strategy that you might utilize in this specific indication?

Jennifer Lee: 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 market research. We’ve gathered feedback from our field teams, have started engaging with physicians just around better understanding the HO market. The pieces that 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 feedbacks from the physician population.

So, those two pieces are sort of ripe 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. 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 set with the data that we have to be able to hone us down to which of those, even within the specialty, is much higher than, like I said, the breadcrumbs that we started with in BBS where there was no ICD 10 code, they’re scattered amongst various different physicians. So, I think those dynamics make it a more interesting and exciting potential launch for us.

Ram Selvaraju: Great. And then secondly very quickly, in the wake 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 has kind of signaled an evolution in your thinking about how best to penetrate that opportunity. Thanks.

David Meeker: Yes, no thanks. So, one, we’re thrilled to have the rights of the China back. I just feel good about having global rights here, number one. Number two, we absolutely are expanding globally. We’re really excited about the Japan opportunity. We haven’t talked about that on this call, but that’s going to be a very meaningful opportunity in HO. China itself, we learned a lot in our partnership with RareStone and it was incredibly helpful in that sense in that 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 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 China and Asia and a larger sense, Taiwan, countries are – South Korea, I mean, those are meaningful opportunities and we’ll work our way through that and keep thinking about what’s the right strategy for China.

Ram Selvaraju: Thank you.

Operator: Our next question comes from Paul Matteis with Stifel. You may proceed.

Paul Matteis: Hey, sorry about that. I think I missed out in the queue earlier. Appreciate you fitting me in. Just going back to bivamelagon 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 seeing 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 3. So, how do you think about the bar for this shorter phase too? Thank you.

David Meeker: Yes, that’s a great question, Paul. Thank you. So, on the safety side, again, 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. 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 is quite reassuring, number one. And then two, your question on the bar, it’s a good one and which I – why I always don’t – I don’t like being boxed in, particularly around data. There’s always context around data and particularly in a rare disease.

I mean, the means are – I’m not at all interested in the mean value so much. I’m very much interested in patient by patient. And if the mean doesn’t get to 10%, but you can explain a 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. One way of looking at this is our Phase 2 data, if you remember with setmelanotide was 16 weeks and they did hit – almost all of those patients had 10% or greater or were on track to lose 10% 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 16 weeks is relatively short.

Paul Matteis: Makes sense. Thanks a lot.

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

David Meeker: Okay, well, thanks, everybody. Had a long call this morning, a lot of questions, so appreciate that, and we look forward to our next update.

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