Good morning everyone. Thank you for joining the 25th Annual Needham Healthcare Conference. My name is Joey Stringer, and I'm one of the biotech analysts at Needham & Company. It's my pleasure to introduce our next company, Rhythm Pharmaceuticals. Joining us today from Rhythm is CFO Hunter Smith and Head of Investor Relations Dave Connolly. For those of you joining on the webcast, if you would like to ask a question, please do so at any time. You can submit a question using the chat box feature at the bottom of your screen. With that, we'll get started. Hunter and Dave, thank you so much for joining us today.
Joey, thank you. It's great to see you, and appreciate your invitation from Needham & Company, and particularly appreciate the years since the beginning that you have followed and covered our story. Thank you so much for all the work that you do for Rhythm and for our investors.
Great. Well, it looks like once again, another pivotal year. 2026 looks to be another one of those for Rhythm. I guess before we jump into the details of the pipeline, what are the company's top priorities here, and can you briefly touch on the key milestones and catalysts for the rest of the year?
Sure. The biggest priority, and the thing we've been working towards for nearly four years is the opportunity to launch IMCIVREE for the treatment of acquired hypothalamic obesity in the U.S. Acquired hypothalamic obesity is a rare severe obesity caused by damage to the hypothalamus arising from brain tumors, surgery, radiation, trauma, or inflammation. That injury disrupts the MC4R pathway's regulation of hunger, satiety, and energy expenditure. It accelerates weight gain, which is in a way distinct from general obesity. There is a significant unmet need. Over 10,000 patients in the U.S., an incidence of 500 or so new cases every year. Our launch is underway. We upsized our sales force from 16 to 42 territory managers and significantly built out our patient support network. IMCIVREE is the first and only approved therapy for acquired HO. We have a lot of excitement about this launch.
I think we'll talk about it more as this goes on, but t hat is our big priority. We are also expanding IMCIVREE for the treatment of HO in Europe and Japan and other countries outside of those regions, but those are the two big ones. We got a positive CHMP opinion a little earlier than expected, in Q2. We're expecting a launch in 2027. We think the epi is comparable to the United States in Europe. We'll give more details on our Japan process in the Q1 call, but we've obviously had positive interactions with the Japanese PMDA, and very strong efficacy by including a Japanese cohort in our full 142-patient data set. We're excited about the opportunity there. That market is actually potentially larger on a population-adjusted basis than the U.S. and Europe on the basis of a higher incidence of craniopharyngioma.
We think it's about a 5,000-8,000 patient prevalence. We are building our own team there, and we have confidence in our own ability to execute. Beyond that, we are expecting to initiate a phase III study of bivamelagon in AHO towards the end of this year, and we're expecting data in HO for our weekly injectable RM-718 in HO later this year as well. Both of those pipeline compounds, in addition to being an easier or more preferable administration route to a daily injectable, they are MC1R sparing, and so they avoid the hyperpigmentation associated with setmelanotide, which certain patients find is a very negative adverse event. We're also active in Prader-Willi syndrome. We believe that the biology of the disease lends itself to potential rescue or partial rescue by MC4R agonism.
We gave an interim update of about 8 patients in December of last year, and we're going to give a full update of all patients who've been treated sometime around mid-year. We had 1 patient drop out, so we have 17 patients on therapy, including the ones we already read out previously, and it's a six-month open label study. Separate from that, we're enrolling patients with PWS in a phase II. It's a multiple ascending dose in patients with Prader-Willi syndrome. That is for RM-718, the weekly injectable. We continue to broaden out the last pillar of our MC4R franchise, which is the treatment of genetic disorders.
We had a bit of a setback with the failure of the MASH study earlier this year, but we learned a lot of positive things, particularly about response rates in POMC, Hets, and SRC1, and other genes from our DAYBREAK trial. We're exploring better ways to understand who has loss of function, who does not, and we want to continue to try to meet the unmet need for those patients.
Great. Hunter, you mentioned you gained approval in HO, IMCIVREE did, last month. I guess, can you outline the commercial opportunity in this indication? And separately, what are you hearing and seeing in the early days of the launch there?
Sure. Even though HO is rare, prevalence is upwards of 10,000 patients in the U.S. The opportunity is significant because the baseline diagnosis rate is higher, even though it's not uniform like some rare diseases like a CF or something, or PWS or something like that. The vast majority of patients, after their hypothalamic injury, have some form of endocrine insufficiency, hypopituitarism, diabetes insipidus, and things like that. They continue to be under the care of an endocrinologist. What we have been doing is working hard to educate endocrinologists about HO to the extent they're unaware of it and working with them to be in contact with them to diagnose patients. We expanded our field force from 16 to 42, significant upsize, and we leveraged claims data that indicated about 5,000 endocrinologists may have an HO patient.
We think some 50% or so of that number have two or more, may have two or more. What we've been trying to do is prioritizing that second subset, try and get as much reach to that subset as possible. Help to understand, are they well-educated on the disease? What is their disease awareness? Do they have patients in their care? Have they made any diagnoses, or are they prepared to make diagnoses of patients? And then we'll work to help them with getting patients on IMCIVREE over time. What I would say is we are a couple of weeks in. The reception's positive. We're enthusiastic about how things are going. It's obviously very early, so we don't want to comment because it's way too early to call a trend.
Sure.
We feel positively about how things are going.
You've had this successful launch in BBS. I'm curious, can you compare and contrast the HO launch to the BBS launch, and what are the biggest similarities and differences that investors should be aware of in terms of how patients are ID'd, coverage, market access, things like that, and then m aybe as a follow-up to that, in terms of revenue, how should we think about the HO launch relative to what we've seen in BBS, where it has been a relatively steady quarter-over-quarter increase in revenues?
Sure. BBS is a little bit more of a classic rare disease in the sense that you're starting with a very low diagnosis rate, and there's not a natural clinical algorithm where a patient is diagnosed and then handed over to an expert center. When we started, we were finding patients, and their conditions include rod-cone dystrophy, which causes vision impairment. There's renal disorders. There is obesity and hyperphagia. There's polydactyly, things like that all lead one, and genetics can help with that diagnosis, but ultimately it's a clinical diagnosis. When we started, the diagnosis rate was very rare, and we believe that our company is responsible for most of the increase in diagnosis of BBS since IMCIVREE's been approved, and t hey were pinging around the medical system.
You'd find them in primary care, you would find them in obesity specialists, but you would find a lot of them in renal specialist settings, nephrology settings. You would find a lot of them in vision settings. They were pinging around the system. What we've found since then is over time, the referral patterns are starting to improve, and people are out there looking to diagnose and treat the obesity of these patients. If we estimate that prevalence as 4,000-5,000 patients, we estimate a very low diagnosis rate. We gave a pre-launch estimate that we'd sort of identified 250 patients or so 5%-ish. Whereas, we gave a number last year that we'd identified up 2,000 or so suspected or diagnosed HO patients, and we've grown that number since then. We're starting from a higher diagnosis rate.
We're starting from a greater concentration in a single specialty. The addition of the brain tumor is a very profound life event. The follow-up medical problems are very significant. We think that lends itself to a more rapid diagnosis and disease recognition. Then lastly, our data, our efficacy data in HO is really profound. It is more standout, to be frank, than our BBS data, even though we've had a great effect in BBS. We think that gives us an opportunity for a faster uptake than BBS in HO.
In terms of the launch metrics, things such as script data, revenue, what do you plan to provide investors going forward? Would you provide a breakout of revenue between IMCIVREE indications or perhaps at least for HO?
Revenue is very difficult because it's the same therapy, right? There's nothing, putting my pseudo accountant's hat on because I'm not an accountant, but putting my accounting hat on, there's nothing in our financial systems that can differentiate between revenue from an HO patient and a BBS patient. You would actually literally have to be saying, "That script was with so and so, and that script was with the other person." And that's not auditable. The scripts, very clear. We will be breaking out HO scripts and start forms-
Got it.
When we start reporting launch metrics. Revenue, no. We expect that we will have a good understanding of what is driving the shift in revenue, and we can talk about it qualitatively. We will talk as we've talked about the change in patient numbers and things like that. We will talk a lot about the writers, depth and breadth and reach and things like that, and what the reception is like, both quantitative measures and anecdotal measures.
Last one on HO. In terms of the commercial opportunity in U.S. versus Europe, how do you anticipate the relative split of, say, peak revenues would be between the U.S. and Europe?
It's a good question, and again, there are a lot of factors that go into that. I think all other things being equal, the price on average is lower in the E.U. We are still getting rare disease pricing. You also do not have the ability in the E.U. to increase price. Every new indication, you get a price reduction, and in some countries, you're actually asked to take a price reduction just over time. So that factor alone, all other things equal, would indicate that you would have that sort of haircut. Currency matters. We've been in the period of consistently declining euro versus the dollar. If that changes, obviously, you do have a stronger performance on a currency-adjusted basis. Lastly, what you don't have in the European countries is any free drug. Right?
Every patient is fully reimbursed, and so while your headline price per patient may be lower in the EU, they are reimbursing every patient. In the U.S., we definitely have patients who don't have coverage that we provide free drug for, so.
Got it. Great. Well, switching to Prader-Willi, the Prader-Willi program, you had some-
Mm-hmm
Really good data last December. You mentioned you're guiding for some additional data. I believe it's middle of this year, but
Mm-hmm
... Correct me if I'm wrong. What data do you plan to announce in that top-line readout? You mentioned the number of patients, but just to level set our audience, time points, endpoints, et cetera.
Sure. Like we said, we're going to release that data around mid-year. We will have 17 patients who have been on therapy for six months or more. We think there is a significant unmet need in PWS, even with Vykat, which affects some of the benefits patients on some of the behavioral aspects of that disease. No approved therapy has been shown to reduce body weight. We did disclose data in December on about eight of 18 patients who had reached three months, and five who had reached six months. We'll have 17 have reached six months. That data was 1.3%-4.8% BMI decreases, and at six months, the two patients had cleared the 5% BMI reduction targets.
Yep.
DEXA scan data was significant. Importantly, hyperphagia scores as measured by the HQ-CT had shown improvement in six of seven patients with an elevated baseline. We will absolutely be showing BMI, we will absolutely be showing HQ-CT, and to the extent we have it available, we will talk about the DEXA data. I think we have always stressed the nature of rare disease. The individual patient outcomes are really important. They tell a better story than looking at a mean. There are a number of things that can confound a mean, but understanding the patient benefit through the individual stories, as we've always done, is what we plan to do in this case.
In terms of the reduction in BMI, I guess, what does a clinically meaningful or relevant reduction in BMI in PWS, relative to say, BBS and HO, what is that? Maybe help us or help define that. Then as a follow-up, what do you consider the bar for success in this upcoming readout, given that we did see BMI reductions around 6% at month six. What's a reasonable expectation for BMI reduction from the more fulsome data set at six months? Then, what do you think it would look like at one year?
Sure. Excuse me. The allergies are killing me, but I'm glad it's spring. We believe that anything above a 5% placebo-adjusted difference in BMI over a 52-week trial would be supportive of approval. Weight gain in PWS in the absence of very strict caloric restriction, which is what is practiced in some of these group homes for these patients, is the norm. The other longer-term PWS data that's target weight, there was one trial, a drug called beloranib at six months showed placebo-adjusted weight decreases of 8%. The actual weight loss was 4%-5% in the active arms. Right? The placebo group gained weight. I think that's the baseline expectation. That trial, despite its efficacy, was stopped early due to thrombotic events. That drug was discontinued, but there was a lot of enthusiasm for the efficacy data that was shown at that time.
Got it.
The other interesting question which has not been asked is, how much obesity is there in the PWS population? I've heard varying estimates. We think it could be 50% of the PWS patient population is obese, but the need to be on severe caloric restriction in a group home setting is a driver of patients who are not obese. You have a very, very severe environmental restriction that keeps them from becoming obese in many cases.
Would the mid-year, the upcoming readout in PWS, assuming a positive outcome, would that give you the green light for a phase III? What would a potential registrational trial look like?
We believe, we believe we saw a strong enough signal in the interim phase II data to begin preparing for a phase III. We are confident that we will be able to enter phase III. We believe it will be a 52-week placebo-controlled study. Site selection and execution has to be done very carefully. We would obviously be looking similarly towards some endpoints around BMI change, HQ-CT improvement, and something around change in fat mass. I think the one question we have, because we're also pursuing RM-718 in an exploratory MAD Part D study in PWS patients. I think the question we're thinking about, how much progress has that shown, and what is the best one to take forward into phase III? I think our base case.
Yeah
Is still we would go with setmelanotide, but if we're seeing really good results with 718 as a weekly injectable that is MC1R sparing, it may be a better drug in the long run for these patients.
Got it. Certainly makes sense. I guess whether it's 718 or setmelanotide, as you look towards the PWS treatment landscape, what would differentiate your drugs from, say, Vykat? Would you potentially be competing for the same types of patients in the marketplace?
I don't believe that we need to think too much about competitive positioning. These are complementary mechanisms. Both have shown improvements in behavior. We will have eight of the 18 patients entered the phase II study on Vykat. We will have eight with and nine without. Many patients are contraindicated for Vykat. As a result, they may enter with lower baseline HQ-CT than the patients who are not on Vykat. We'll see.
Yeah.
Vykat hasn't been shown to have any effect on weight improvement, weight reduction, BMI improvement. That's our primary goal. We believe they can be used together, and so, again, I think talking too much about competitive positioning between the two may be premature.
Got it. Fair enough. Curious, what are your takeaways or learnings from Soleno's launch of Vykat and PWS as it relates to the potential opportunity for Rhythm in this indication? What are the read-throughs to PWS market as you see it?
I think the biggest read-through, and I think this was thought to be the case before the launch, and the launch demonstrated it, is that this is a well-organized community of caregivers and physicians who are really, really urgently in need of disease-modifying therapy. For those who believed that Vykat would be potentially impactful on the difficult behaviors associated with hyperphagia in PWS patients, there was a lot of enthusiasm right out of the gate. That speaks to, again, the high diagnosis rate, the fact that many patients are cared for in a group setting, and that the caregivers have to be so intimately involved with the care of their patients.
We believe that those patterns would also be very present in any launch of setmelanotide, which again, would be targeting some different aspects, albeit complementary on hyperphagia, but targeting some different aspects of their metabolic health.
I guess a somewhat related question here, but can you give your thoughts on the recent proposed deal between Neurocrine and Soleno for $2.9 billion, the centerpiece of which was DCCR for PWS. I guess what are the read-throughs to Rhythm, and what does that deal say about the PWS space in general?
I think the primary read-through is that Neurocrine believes that the unmet need in PWS is very significant, and having a therapy that can address that partially is a very meaningful and important rare disease opportunity. We agree with that.
Great. Well, in terms of some of the other programs, you certainly have setmelanotide, the oral bivamelagon, and RM-718 clinical development, as you mentioned, going on in parallel with these assets. I guess, can you just summarize your lifecycle management strategy here, the LOE protection that you have, and what would an ideal lifecycle management outcome look like?
Sure. Our composition of matter for both RM-718 and bivamelagon extends into the 2040s. It depends on timing of patent term extension relative to approvals. We are looking to get one of the next-gen agents approved for all current setmelanotide indications, effectively replacing the daily injectable with options that we believe patients will view as superior, primarily from an administrative standpoint and from an AE standpoint. The efficacy, we hope that the efficacy will be comparable. Some cases, it may be superior. We'll see. Obviously, a daily oral and a weekly injectable are really important. Both are specific to the MC4 receptor. They don't hit the MC1 receptor, which causes hyperpigmentation. We did see some very localized instances of hyperpigmentation in the bivamelagon phase II study, but nothing meaningful that caused treatment discontinuation.
Great. Hunter, the competitive landscape, there's not a ton out there, but I guess, can you assess any competitive threats from companies that are working either in and around the MC4R pathway space?
The only therapy we know about that's been, you know, dosed clinically has been Vyleesi from Palatin, which was originally for female sexual dysfunction. It's limited to eight doses per month because it does trigger a temporary increase in blood pressure and a decrease in the heart rate. It's quite limited. They've talked about having other potential clinical compounds, but as yet have not. We know of no other clinical program in MC4R, but success always attracts competition, and we expect there will be some.
Got it. Lastly, moving on to some financial questions, Hunter. Profitability. How big of a near-term priority is this, and what does the path look like to profitability?
It is not an intrinsic priority for us. We have what we believe is an incredibly rich opportunity to invest in high probability of success research and development for the bulk of our R&D budget, i.e., things that have existing proof of concept for the MC4R mechanism. We also will continue to work on additional translational research to look for new opportunities for IMCIVREE, the two pipeline compounds, as well as the other stuff we're working on in the preclinical setting. We have talked about, for example, a program we brought in to target congenital hyperinsulinism, and we haven't talked a lot about that, but we're hoping for some news in the next year or so. That's our top priority, and we don't believe that resources are a constraint on that.
Obviously, we ended the year with a lot of cash, around $390 million. Our OPEX guidance, non-GAAP OPEX, which is a proxy for cash burn, is around $400 million at the midpoint. Certainly, using various street-based assumptions, we can flip profitable in the next couple of years. We're not guiding on that front.
Yeah.
You know, but our preference is to continue to invest in the business where we have good opportunities.
Would you consider deploying some of that capital to bring in external assets, BD, or do you think a better capital allocation plan is looking to expand indications within your current assets?
Our vast preference is, you know, given that we are the only company with an approved MC4R program, clinical MC4R program, to continue to exploit those opportunities and find more patients who will benefit from MC4R agonists.
What's the current cash position here? What are your expectations on cash runway?
Yeah. We've been saying for a while now that we have greater than 24 months of cash equivalents. We think that it takes us past the need to raise for the purpose of maintaining positive cash balances. We may need additional liquidity in the coming years, depending upon the trajectory of sales and the degree of investment opportunities that we see.
Last one from me, Hunter. What's your vision for the company over the next five-10 years? Do you want Rhythm to become one of the leaders in the obesity space, or is the vision more nuanced than that?
Yeah. I would say we are the global leader today in rare MC4R pathway diseases, but our desire is to realize what that potential is, and I don't think we fully understand the totality of its potential. It's very important for us to execute really, really well everywhere in the world on the acquired HO opportunity, develop one or more assets to treat Prader-Willi, continue to work on the genetic pillars, and then build a true multi-indication commercial franchise around the world with deep expertise in this pathway. We are a rare disease-focused company. We want to play where our therapies have a disproportionate impact on patients for whom no other therapy is really available.
Great. Well, Hunter and Dave, thank you so much for participating. It was an excellent discussion.
Thanks as well Joey. Great to see you, and we'll talk again soon.
Thank you everyone for joining us on the webcast. Have a good day and a good rest of the conference.