That's the five-year-old in me coming out. Well, thanks everybody for joining us here. I'm Seamus Fernandez, one of Guggenheim's Biopharma analysts. We're here at the Emerging Outlook Biotech Conference, which we host every year. And I'm thrilled to have Rhythm Pharmaceuticals CFO Hunter Smith here with us. Many of you know the sort of story around Rhythm. But I'm actually gonna turn it over to Hunter to tell the story, quite a bit better than I will. But it's been an exciting, you know, 12 months, for sure for Rhythm. You know, and excited to continue to see more success ahead.
Thanks so much. First of all, Seamus, it's great to see you. Happy New Year. Thank you so much to the Guggenheim team for hosting this terrific event. It's super to see, you know, all of you investors here and the enthusiasm that continues to build around biotech. We're particularly excited about what's going on at Rhythm Pharmaceuticals. We're a company dedicated to the treatment of rare neuroendocrine disorders. We are particularly focused on the MC4R pathway, for which our approved therapy, IMCIVREE (setmelanotide), is the first-ever approved agonist of the MC4R pathway that's been shown to be both safe and efficacious in patients. We are approved for about three indications. I'm sorry. We are approved for three indications with a fourth coming, with a PDUFA on March 20th, which is the most significant for the company. That's hypothalamic obesity.
We also have some recent interim phase II data in Prader-Willi syndrome that we're particularly excited about. And lastly, we have two pipeline compounds, an oral small molecule MC4R agonist called bivamelagon, as well as a weekly injectable therapy called RM-718, both of which we think can particularly be attractive to patients for their improved convenience dosing profile as well as their better tolerability.
Great. You know, and maybe just to sort of, you know, set the ground level here, obviously MC4R, a novel asset, you know, but everybody wants to talk about GLP-1s and obesity. What is it about the sort of whether it be hypothalamic obesity, or, you know, BBS, Prader-Willi, that really has GLP-1s and those targets not particularly effective? What is it that's so unique about the MC4R pathway in these patients?
So we like to think of what we are doing as effectively hormone replacement. So IMCIVREE setmelanotide is an analog for alpha-melanocyte-stimulating hormone, which is produced by the POMC gene cleaved into its final form by the PCSK1 gene and then agonizes the melanocortin-4 receptor. This is a bit like a thermostat. We all produce it. It goes up after a meal and goes down when we're hungry. And for patients who are deficient in the pathway, they simply do not produce enough of alpha-melanocyte-stimulating hormone. So that is why in the patients most profoundly affected by a POMC-related deficiency, those would be POMC nulls as well as what we believe is the primary driver in HO patients, their response is very quick, instantaneous, and pretty uniformly positive. The consistency of response across these patients is very positive.
They simply do not produce the hormone which regulates satiety and resting energy expenditure in the hypothalamus. GLP, which is, you know, an incretin produced in the gut, you know, obviously can work to constrain some forms of appetite. But if you have that absence of central signaling, that will still be there despite some of the peripheral, mechanistic aspects that, you know, cause people to want to eat less or maybe feel, you know, somewhat to feel full in the gut. And that, I think, is the critical difference and why GLPs often don't have an effect in our patients or they have a more limited and short-term effect in our patients.
Got it.
It's also why we've seen patients who are on setmelanotide as background therapy, you know, potentially have an additional response to GLP-1 as long as it's in place.
Got it. Excellent. So, you know, obviously, great to have you here to talk about kind of sales trajectory and, you know, the opportunity as we move through BBS, and, you know, the LEPR, POMC opportunity. Help us just maybe understand the kind of base of sales growth, how we should think about that. And then as we add AHO to the mix, how should we be thinking about the incremental kind of launch characteristics?
Sure. So we have experienced, we're about three plus years into launch of Bardet-Biedl syndrome. We have launched it globally. We do have some, HO patients on treatment today due to early access programs in France and in Italy. But BBS is the primary driver of our growth. And last quarter we reported about $57 million in sales. And that's shown of a growth if you average the two quarters prior, it's been about 9% quarter-over-quarter growth for the bulk of last year. That was backed by 10% growth in reimbursed patients on therapy in Q4, 7% increase in the cumulative number of writers of BBS prescriptions. BBS patient population is quite dispersed, and we tend to find them in pockets rather than at specialized centers.
What's been good and what's exciting both in the U.S. and outside the U.S., and by the way, outside we're either approved, reimbursed, or we have patient access in 25 countries now.
Yep.
What's exciting about that is we continue to see BBS patients being brought to diagnosis, being identified for Rhythm, and physicians continuing to prescribe IMCIVREE for those patients. So our patient numbers continue to grow. What we've liked to say is that what's the probability that we could get to 1,000 patients on drug in the United States in a 5-6-year time frame, at an average of $300,000 a patient in terms of a net price? You know, it's pretty achievable in a 4,000-5,000-patient epidemiology. So that in and of itself points to a $300 million peak sales opportunity in the U.S. alone. And then you can add ex-U.S. to that. So it makes for a pretty exciting opportunity in BBS by itself. And we expect that growth to continue.
When we turn to HO, there are some different characteristics that make it a more compelling and more attractive long-term opportunity. And obviously there's the perception in the street and the estimates for much greater potential value from that indication. First and foremost, it is a larger epidemiology. So our calculations, which are both epidemiological estimates, and then they're supported by claims data. And then that claims data has been in part validated by the reach of our U.S. sales force, is that we think there are upwards of 10,000 patients with HO in the U.S.
Yeah.
That's acquired HO. There's also congenital HO, which is a separate category we're doing a separate study on. Those patients, the vast majority of those patients have some form of hormonal insufficiency driven by the treatment, that damages their hypothalamus and causes the HO. And so they're often getting some form of pituitary hormone insufficiency or diabetes insipidus or some types of things, which keeps them in regular contact with an endocrinologist. Therefore, the patients are more diagnosed.
Yep.
They are not uniformly diagnosed. It's not like a CF or PWS level diagnosis rate, but they are more diagnosed and they are treated in a setting that is concentrated with endocrinologists, not necessarily in specialty centers. They are dispersed because for the most part all they need is the hormonal supplementation, because up until now the obesity has not had a therapeutic option. So we will find them somewhat easier to find in larger numbers. And therefore there's a prospect for a, you know, a significantly higher, total long-term sales or peak sales opportunity than BBS.
Okay. And then in terms of just the identification of patients, what is the kind of commercial workup that the team at Rhythm has done and is doing, in anticipation for the March 20 PDUFA date? And again, maybe we can just sort of lay the foundation here. We're sort of assuming everybody knows how good the AHO data was, but maybe you can just back into that a little bit as well.
Sure. So we had a 60-week, including a titration period, 2-to-1 randomized double-blind placebo-controlled study, comparing patients on setmelanotide to patients on placebo. That was read out in April of last year. We saw patients on setmelanotide see a 16.5% reduction in BMI, patients on placebo gain weight, and therefore the placebo-adjusted difference was about 19.8% at 52 weeks on the maintenance dose or the full dose. So very, very compelling data. The BMI reductions, hunger reductions were also consistent across age groups. The number of the percentage of responders was very high, so 80% of patients having more than a 5% BMI reduction, 60% having a more than 10% BMI reduction. So very compelling data.
The other thing that was interesting, it's a bit of a digression, was we had a significant number of patients who both had prior GLP-1 experience but were not on GLP-1 therapy at the time of the study, as well as patients who were on concomitant GLP-1 therapy in the study but were stable or increasing in their weight when they entered the study. And those patients had, on average, actually a higher level of BMI reduction, more in the mid-20s than the patients who were on just on monotherapy. So again, a very large study, very well controlled, very powerful picture, of the impact of setmelanotide on HO patients. So with that, we began our, you know, commercial building efforts actually in anticipation that that would be successful.
And then we commenced the hiring and recruiting process right on the heels of the release of the data, such that we now have gone from 16 salespeople in the U.S. up to 42, and we had them in the field and trained, as of October 1st of last year. That was in anticipation of an earlier PDUFA date in December, which was deferred by the FDA to March. That plus the efforts of our MSLs who were there, obviously preceding the hiring of the sales force, they have been out there using claims data to profile patients in the care of those physicians. So we use claims data.
There is no ICD-10 code for hypothalamic obesity, but we use claims data to look for an index event, which is usually the tumor diagnosis, a surgery to deal with the tumor, some form of hormonal insufficiency, obesity, and a recency factor that they have visited an endocrinologist during that period of time. That data was reinforcing of our epidemiological calculations. That was the basis on which we sized the field for us. That's the basis on which we segmented the physician population, the endos that we've targeted, about 5,000, of which about 2,500 have three or more potential HO patients.
Okay.
Then the MSLs supplemented last October by the field force have been out profiling those physicians and identifying patients.
We communicated in November that even based on that modest reach, that limited time in the field, they had identified upwards of 2,000 suspected or diagnosed HO patients in those tier one and tier two physician practices.
Wow. Okay. And what are the governing factors to prevent those patients from really rapidly going on to drug? If they're identified, what needs to happen in the sequence along the way for them to get setmelanotide?
So there are several factors, some of which are specific to this particular, you know, this particular situation and some of which are general. Right. Obviously, physicians need to have an awareness of the disease and an urgency to treat. I've been a little surprised that HO is not more widely understood among endocrinologists than it is. I ran into a college classmate who was an endo down in North Carolina, and I told him about our data. I ran into him at the endo conference, and he actually asked me what hypothalamic obesity was. But if you think about endocrinology, it's a complex, very in-demand specialty. Obviously, there's a lot of diabetes care. There's lots of other things that are part of the practice, and you don't necessarily encounter these patients every day.
So there's a physician education and, you know, helping to drive the need to and the desire to diagnose patients. That's a component of it. Then there is the overall pressure, like many specialties feel, that, you know, it is very hard to get an appointment with an endocrinologist. They are booking a year out and those types of things. So if they have a patient that's diagnosed, that's one thing. If they have a patient where we've helped, you know, we've looked at the claims data, this patient, is this patient in your practice? Do you think this patient might have HO? They might say, yes, I'll bring him back in and see if I can reach that diagnosis. That can take six weeks. It can take nine months.
Right. Okay.
So those are the major factors. Those are the factors, of course, that just drive the ability and the willingness to prescribe. Then you have the various factors around conversion of a script to a reimbursed patient where you have, you know, the traditional process, which I think will be a bit easier given that we've been in front of a lot of payers already, but it still takes time. P&T committees have scheduled meetings, and the schedule doesn't change because you have a new approval. Right. So getting those policies in place at the payers and getting those reimbursement decisions through is going to be a time-consuming process that will also affect the dollar trajectory of launch in the way it lags, you know, in the way it potentially lags the Rx being written. Right.
And then the last thing I would mention in the category of things that may affect the trajectory of launch is just there are very specific prohibitions, a statutory prohibition in the case of Medicare against the reimbursement of weight loss therapies. As of today, we are classified solely as a weight loss therapy, and therefore we cannot get Medicare patients reimbursed. We think the Medicare population in HO may be higher on an age basis. So in BBS, we had some disability-based Medicare patients, because they go blind. But we had virtually no or a handful of age-eligible Medicare patients. The incidence of tumors is more varied in HO, and therefore we may have more age-eligible Medicare patients that may drive a more variable free drug percentage than we saw in the case of BBS.
Okay. And does the establishment of the CMMI for GLP-1 drugs kind of change the dialogue as it relates to Medicare at any point for, AHO, in your opinion?
I don't think it's potentially helpful, but I really have no idea.
Yeah. Okay. We won't see you negotiating, publicly, I guess.
Yeah.
So, you know, let's talk. I mean, I think we've covered a lot. You know, you did have the minor delay with the PDUFA. You know, in terms of disclosures after the fact, I think it was one of the most revealing disclosures. Maybe you can just help us understand that because, you know, when we saw that, we were shocked that there was a delay. But I know not offering any specific opinions, but maybe you can just review that update.
Sure. So, we measure the change in BMI for all patients, but for patients that are below 18 because they are growing, we calculate a BMI Z score. Therefore, the age of the patient is significant. In order to comply with European patient privacy regulations under GDPR, we cannot know the birth date of the patient. So we assume that the birth date of all patients is June 30th of the given year in which they are born. The FDA, at a certain point, and again, this is an sNDA under breakthrough designation. The FDA asked us for a supplemental analysis to look at the BMI Z score data, but assume that the patients' birthdays were January 1st of a given year, as opposed to July 30th or June 1st, whichever it was of the same year, and then reanalyze the data. We performed that analysis.
As you might expect, it had no significant impact on the various endpoints for those patients. But nonetheless, it was a pretty thick amount of paper, right, for them to reanalyze, and they constituted a major amendment and deferred the PDUFA date.
Okay. Understood. Pretty straightforward.
Yeah.
You know, maybe we can now advance to Prader-Willi.
Sure.
You know, you guys have, I guess, that there are some unique characteristics here. Maybe we can just talk about the rationale for targeting the MC4R axis in Prader-Willi. And if there are supportive genetic data to kind of help us along the line there.
Sure. So in Prader-Willi syndrome, patients lose a chunk of chromosome 15, and it causes a lot of very severe clinical manifestations, cognitive manifestations, and other things. And there is one of the genes that is knocked out in that process is called MAGEL2, which is upstream of the MC4R pathway. And so there is a perception that if that is causing a reduction in production of alpha-MSH, that therefore we have the potential to rescue that deficit. It may not be the totality of the cause of obesity and hyperphagia in these patients, but it certainly is the potential to rescue that deficit. So we had studied both Prader-Willi itself very early in our life cycle where we did not have a lot of long-term dosing approval.
What we saw in a pretty complicated study was that the patients who were on setmelanotide for, I think it was eight weeks at a 2.5 mg dose, which is a relatively small end in a multi-armed study. Those patients were trending downward at the 8-week mark.
Okay. Separate from that, we did a study, a phase II study where we were looking at patients with point mutations in a variety of genes. We called it our Daybreak study that were associated with the pathway. And the patients with validated MC4R, MAGEL2 deficiency also did quite well on setmelanotide in the study. So that gave us the confidence in the biological rationale. We also decided to potentially or to increase the dose to 5 mg from 3 mg. So, given that, we've always had that headroom and we thought we would this was an opportunity where more might be better. So we did an interim look in December and we had data in about three patients who were out six months and I want to say five patients who were out as far as three months. One patient did not get very far and continue.
But, you know, two of the patients out six months were doing quite well. And several of the patients that were out for three months were doing well as well. And we saw both improvements in BMI and HQ-CT, and even the non-responders, excluding the one patient who had dropped and who was not compliant, had other positive clinical manifestations, whether it's HQ-CT but not necessarily weight or whether it's improvements in a reduction in fat mass.
Got it. Okay. So remind us, you know, just sort of what this means to setmelanotide and then, you know, the overall, kind of, pipeline opportunity. How big is PWS? You know, there are other drugs that have been approved recently, you know, for PWS. How are you guys approaching development going forward? Obviously, you have additional data coming as well. Maybe just remind us what's next in PWS.
Sure. Let's start with VICAD because it's an important question. The VICAD is an extended-release diazoxide and we have, you know, studied that mechanism internally in terms of how it might work with MC4R agonism. The belief is those mechanisms are complementary, if not synergistic. Yeah. As a result, we had two patients in the interim readout who were on background VICAD therapy and in the 18-patient data that we expect to read out, you know, at some point in the first half, there will be eight patients on background VICAD therapy. Okay. We see no reason—it will be an interesting access question, but let's put that to the side. We see no reason why patients cannot benefit from both therapies, to the extent that they are not contraindicated for VICAD.
Many patients will be contraindicated for VICAD due to diabetes and other considerations. Okay. So that's that component. So then to the sort of next steps, we obviously plan to, you know, get to the end of the phase II, read out the data on 17 patients of the 18 because the one discontinued, and share that data and then, you know, and then speak to the FDA about a potential phase III design. At the same time, we have RM-718, the weekly injectable, and that therapy we believe is better suited to the PWS population than our daily oral, both because of, you know, pill size and there's some challenges with small with swallowing. We are working on that from a form dev perspective, but it is more complicated and overall from a compliance perspective.
So we have started a phase I, multiple ascending dose cohort in Prader-Willi syndrome for RM-718. Okay. We'll update on enrollment and potential timelines for that later in the year.
Great. Just remind me, as we wrap up, when we're likely to see the data in PWS and then also, you know, you've talked about the runway from a cash perspective to profitability. Maybe just remind us where we stand on those lines.
So again, the setmelanotide six-month phase II data we expect at some point in the first half, and we have not given a timeline on a readout of RM-718 yet. We want to see how enrollment goes. And once we have sort of an update on enrollment and where we want to get to, then we'll guide on terms of, how much, how when we expect to read that data out.
Great.
Then in terms of cash runway, we exited Q3 with about $418 million in cash. We are saying that that is at least 24 months of runway and that is a rolling comment.
Okay. Very good. Well, Hunter, thank you so much. Thanks for taking the time. Appreciate the opportunity to have Rhythm here with us again. Yeah, looking forward to a busy period for sure.
Absolutely. Thanks so much.