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

Good morning, everyone, and welcome to the Goldman Sachs Healthcare Conference. We're thrilled to have David Meeker, the CEO of Rhythm, here today joining us. Before we get started, we are required to make certain disclosures and public experiences about Goldman Sachs' relationships with companies that we discuss. The disclosures relates to investment-making relationships, compensation received or 1% or more ownership. We are prepared to read aloud disclosures for any issuer upon request. However, these disclosures are available in our most recent reports available to you as clients on our firm portals. The views stated by non-Goldman Sachs personnel do not necessarily reflect those of Goldman Sachs. Okay. With that done, thanks for joining us, David.

Thank you, Corinne.

Maybe we can just get started on the recent data that you guys reported in HO. It demonstrated a significant improvement in BMI across both pediatric and adult patients. So maybe you could just start by level setting with the highlights from that data.

Sure. So needless to say, we were thrilled with the results. We were optimistic coming out of the strong Phase II, but that was only 18 patients in an open label. So this Phase III was 120 patients, randomized 2:1, 80-40 roughly. And the primary endpoint hit robustly with placebo-adjusted difference of 19.8%. So that was -- 2 things about that. One, very strong, obviously, on the impact of setmelanotide itself on BMI. But also, very importantly, it reinforce what all the KOLs have been saying is that nothing really works in this and that these patients continue to gain weight. And if they just had some drug that can keep them from gaining weight, that would be a victory. So the placebo group gained 3.3%, setmelanotide group decreased by 16.5%. So that was the headline. And then underneath that, if I'm going to go a little deeper here, there's a few other things. What's always been striking to us, and it was true in the Phase II, I mean, we've been happy with the percent change, but we've also tried to stay a little bit out of the GLP-1 wars of the 2% difference is clinically meaningful and people are so focused on that. What's really remarkable about this data set has been the consistency again. So pretty much -- and it's consistent, the concept, the consistency of response is very supportive of this underlying biology, which we think is we're treating people with a deficit in this alpha-melanocyte stimulating hormone. And when you correct a hormonal deficiency, take hypothyroidism, you should have a very high percentage of response. I mean, you're just replacing what's missing there. So the consistency that we saw below the headline data was we had stratified for 3 age groups: 6 to 12, 12 to 18 and 18 and above. There have been some early concerns before the French data came out last fall, maybe it works better in kids than adults. Almost unbelievably, it was identical across all 3, 19% to 20% placebo-adjusted changes for all 3 age strata. So those were -- as I said, we felt really good about the efficacy data there. We can talk about the GLP-1 data also if you want, but there were -- overall, the headline was strong.

Yes. You mentioned the consistency of the data. I guess, you talked a lot about some of the individual patient stories. For the few patients who didn't respond, could you just give us a little bit of color on that?

Sure. So we had -- so 80% of the patients lost 5% or more. And if you take 80% of the 80%, there's about 17 patients who didn't make the 5% at the end. 8 of those 17 patients had to have -- they didn't complete the trial for one reason or another. So they had to have their data imputed. And there's a way the regulators work, FDA specifically. It's a very conservative method. And so you do these simulations and that's how you impute the data, but the data that informs the simulation is strong from a placebo group. So if you have a placebo group that's gaining weight and then somebody drops out of the trial and you impute their data but using the trajectory from the placebo, then obviously, you take a hit there. So 8 of those patients fell in that group, one. And then of the remaining 9, 6 of them either had passed the 5% mark and fell back for one reason or another or they were kids who, despite not reaching 5%, did have a greater than 0.2 change in their BMI-Z score, which for a growing child is clinically meaningful. So I think overall, it was very, very consistent with the fact that most patients respond, not 100%, of the 3 -- so that got us down to 3. Of the 3 patients who didn't fall in one of those 2 groups, 2 out of the 3, and we have documented noncompliance and that we tested trough levels at the midpoint in the trial, the trough drug levels in the midpoint of the trial and at the end of the trial, and both of those values are below level of quantification for those patients.

Okay. Helpful. Maybe on the safety and tolerability side, could you speak to what you saw in the study and comment on some of the serious AEs that popped out?

Yes. So overall, the safety -- setmelanotide was first approved in 2020. It's been out in the Bardet Biedl population since 2022. So -- and we've treated probably well over 2,000 patients. So there's a very strong safety database behind the drug, and what we saw in this population was very consistent with what we've seen across. So it's GI-related side effects for the most part. Hyperpigmentation, where 50% to 60% recorded as an adverse event, but 100% of the patients probably have some change because it's an on-target, off-target mechanism. The serious adverse events were interesting. There was a distinct imbalance there. So we had 27% roughly SAEs in the treated group versus 7% in the placebo group. And as you broke those down, and I've now -- which I didn't have at the time of our original earnings call or the original call following the top line data readout, so I've been through every one of those cases in depth. And it's a series of one-offs and there's really not a good pattern there. For example, there was a couple of COVID infections in that group. We didn't have any -- there was none in the placebo for serious adverse events. But the percentage of COVID infections overall was exactly the same, 11 and 5, so it matched very much the randomization, 2:1. There was 3 infections there, pyelonephritis, appendicitis, cholecystitis, which again there's nothing about the drug or anything. I mean, each one of them had a reason why they might have developed that infection. I think the one thing that -- and I think this will be part of our label and that we will want to make sure people look at, this is a population that's incredibly medically complex. And they have literally 1 to 2 pages of medications they're on between all of the different hormonal replacements that they're on. They may have a seizure disorder. They may have depression. They may have -- so again, there's a plethora of medications they're on. And it's also a group that has never been able to lose weight like this. And so as you start losing weight, if you don't pay attention to the other medications and their dosing, and the most specific one and there was a handful -- there's 2 that stand out. So one is diabetes insipidus, I think now it's being pushed to call it arginine vasopressin deficiency, that's the hormone itself. But that's the hormone that allows you to concentrate your urine. And so it's injured in the hypothalamus and pituitary. It interacts between the 2 of those is how it works. And so if you have diabetes insipidus, unable to concentrate, you have to take your hormone regularly daily, and you've sort of modulated, and the parents and families suggest these or patients adjust it themselves a bit. And you have to hit fluid target. You have to keep drinking a lot. So anything that throws that off, if you get a GI, so it could have -- be GI-related stuff related to the drug, but often just GI stuff in general, your sodiums will bounce out of whack. And so we had a handful of patients who get admitted for that. And then the other significant challenge for these patients is adrenal insufficiency. And that's another, again, hormone that's very commonly -- 80% plus of these patients have diabetes insipidus and a similar percentage have adrenal insufficiency. So any time anything happens, they need to get covered what they call stress dose steroids. And it's to make sure that when we get sick, our cortisol levels rise, and that's what allows us to deal with that assault -- insult. And if you don't do it, of course, it can be a quite serious problem. So those were things that complicate it. And I think the only -- my point is the only link to why there may have been an imbalance in this series of one-offs on the serious adverse events is that their background meds may have gotten a little bit off as they were going through these changes with their weight loss.

So with that in mind, do you anticipate that those patients who have some of these additional complications will still be candidates for setmelanotide in the real world?

100%. So -- and as I said, that -- the percentage of those patients are 80% plus of this total population, number one. Number two, the other thing they told us was, over time, they were requiring less medication and it was becoming easier to manage. So it's not -- it's the change itself. It's not the fact that you have it and you forever can't do it. You just have to be alert as you're managing through these initial changes. And if you remember, this drug, based on our Phase II experience and consistent with hormone replacement, you don't endlessly lose weight. One of the things about, I think, GLP-1s and concern is could you tip over into an anorexic kind of a world where you're just not -- but it doesn't -- we just haven't seen this. And it doesn't -- you don't develop an aversion to food. You just know when you're full. So you leave it. You may leave food on the table but you're...

Can you speak to the compliance you saw in the study? And how do you anticipate that data can translate into real-world use?

So it was high. If you remember, we had about 10%, almost exactly 10% dropouts overall, 14 out of 143 patients enrolled in the full data set, which was very good, much better than we've seen in our other trials. And that was split about half and half between the placebo group and the treated group. And the compliance was 80% plus. So I do think -- this is a group -- a patient population that is used to taking a lot of medications. As we've been told, another injection really isn't that big a deal. They're paying a lot of attention to these other meds. So it's not like you've got something that's intruding in your life. It's just you have your meds. This is now one of them. You have your hormonal replacement. This is now one of them. So I think for multiple reasons -- and the benefit relative to what they are living with, and I think that was -- I'll just make the editorial comment that given the complexity and all they have going on in their life, the importance of this medicine and these changes to their quality of life was pretty dramatic. You might wonder whether you can move the needle when you're just adding another med on 2 pages of medicines, right? This is the issue. It's a big issue for them.

Okay. So then as you think about filing for approval and going through the regulatory process, what are the most important things you want to make sure get into the label?

Yes. We're not -- so all the data, I think it will comfortably go in the label. I don't think there will be a lot of debate or negotiation there. The piece that we've tried before, we'll try again. Hope springs eternal here. It will be helpful to get hyperphagia into the label. And we have it in Europe. As people know, in the indication statement, we have data on hunger in the label. We can quote on it, and it's not part of it, but it will be helpful, for example, as we continue to deal with Medicare. Medicare does not cover today. But anything in the label that would further differentiate us from a sort of interchangeable chronic weight management drug will be extremely helpful. So that's probably our biggest push.

Okay. Then as you kind of move towards that, you also are presumably preparing for commercial launch. What are some of the key commercial tasks you need to undertake between now and when you get to the approval?

Yes. And this is interesting for so many reasons. I'll go back to Bardet Biedl. Bardet Biedl syndrome, as you and I have discussed, is really a classic ultrarare disease, 4,000 to 5,000 patients in the U.S., most of them majority undiagnosed. They're spread out. They don't tend to concentrate in any -- they may see a specialist to get to a diagnosis, but then they get sent back to their primary care because there's nothing for that -- no reason for that specialist necessarily to keep them. So Bardet Biedl is, we've talked about this, steady cadence. And the reason it's steady is you just have to do the work each quarter. You find them, bring them through the reimbursement process and the like. And you don't build a structure to knock on all the doors because you couldn't and it wouldn't make sense. So you try to help build a health care system, a community that is better at diagnosing the patients. And then as many patients as you find, they will find you. We see this each quarter in our -- there's 25%, 30% of physicians writing scripts amazingly still 3 years later who we don't call and we don't interact with. And they're finding us as part of the equation. This is different. HO is different. And the numbers, at least, our current understanding, 5,000 to 10,000, maybe not so different. It's still by every definition an ultra-rare indication. But very well diagnosed is our belief based on the fact that it's a recognizable clinical presentation. They have an insult. There's a before and after. 80% plus of these patients have pituitary insufficiency. And that's really, I think, the key driver is that because of that, they do stay with a specialist. So they need to be seeing an endocrinologist to manage this complex endocrine background. So we're looking at this, it's also rare, but as a specialty kind of launch. And what do you do in specialty? And specialty is a little bit of a dream for pharma, biopharma in the world in the sense that you have big unmet needs, high-value transformative medicines and they are cared for by specialists, so endocrinologists. And we've begun to do the work and -- early on the claims work and the like, and we're validating that claims work with the people in the field. So there's about 10,000 endocrinologists. 2,500 to 5,000 of those probably have well over 80% plus of the patients based on our current understanding. So we'll cover them. And we'll build a sales force that is capable of knocking on all those doors. And it is now a bit of a reach and frequency kind of game. And one of the things, and we've heard these other companies, the challenge is all specialists, but certainly including endocrinologists, who are a bit overwhelmed with the demand, I think, is jamming up that part of the equation. When you have a new therapy for a big frustrating unmet medical need, you can get access. And our early experience is people want to hear about this and they want something for these patients. So we're getting in.

Perfect. Okay. Maybe we can move on to talk about some of the next-generation agents in HO. You've got an oral and a weekly that are currently in development. Maybe let's just start with like high level, how you think about that franchise. What are some of advantages you look to bring for patients with the oral and the weekly program?

Yes. So the initial obvious one is just more convenient daily oral versus daily injectable or weekly injectable. The other is our current setmelanotide does hit the MC1 receptor so you have the hyperpigmentation. And it's not -- 5% to 6% of the total number of patients we treat in a real world discontinue because of the hyperpigmentation. But there's probably a little higher number that they may not call that out as a primary reason for discontinuing, but they're not thrilled by it. So it's not a huge percentage of the patient population, but it's meaningful. And so -- and there's no value to it, so if we could eliminate that. So both drugs were designed with the idea of, "Let's eliminate the hyperpigmentation." So we'll be looking for that in our phase -- this first experience in patients. The developmental strategy behind them is we'll take -- if it works, we'll take both of them in HO. And the wonderful thing, if you will, about the hypothalamic obesity indication is because it's so sensitive from a clinical development standpoint, it's a gift. If we had to develop this for the first time in Bardet Biedl, much more challenging and trying to figure out, are you seeing it, is it real, not real? But this should be pretty black and white. So we'll get -- I don't know if I answered that question, but I'll turn it over to you.

Yes, yes. You can -- it sounds like you're about to go for it, but I was going to say we anticipate near-term clinical data from biva. How should we think about that readout? What do you kind of see as a threshold to move forward with the program?

Yes, my favorite question. I spent months answering that, what do I think is going to be the percent change for the HO Phase III trial. So for the biva trial, what do we expect to see? It's a Phase II, 28 patients, so 7 -- and 4 groups. So 7 patients per cohort, 3 dose groups and a placebo group. So each cohort is extremely small, and have been really trying to highlight for people, they should not be focused on the means. The means may look great. But with only 7 patients, I'm not looking at the means. I'm going to look at 7 individual patients for each cohort. And if 5 look good and 2 don't, then we're going to try to figure out why the 2 didn't respond or whatever. And if we have a good reason for that, obviously, it might be compliance, you're not going to throw the drug out because the mean looks low. You're going to go with the 5 that are telling you it's working and looking good. So that's just how we'll analyze the data. Thresholds, and the way we've been answering this in -- it's a little bit the way we tried to answer it earlier, which is in this population, and now that setmelanotide set the bar, 16.5% in the Phase III itself, 10% or greater is a drug. Now it's 10% or greater in an apples-to-apples. And the reason I say that is, and we've seen this in other situations, I don't think you need to be as good necessarily if you are significantly more convenient, you have other features. And at 10% plus, many patients may be perfectly happy with that, one. Two, you get to 10% not because everybody got to 10%, but because some did much better than 10% and some didn't. So I think just conceptually in thinking about it, 10% or greater is how -- that should be the threshold. Now that's at a year. And we're going to be reading this out at 14 weeks. So what we will try to do, and it's doable, is when we present the data or put out the high-level data is to provide as much context as we can so people can see the apples-to-apples. So what did the Phase II look like? So the Phase II was a 14-week -- sorry, 16-week trial. And so 14 and 16 is close, but actually 2 weeks at full dose is meaningful. So again, we'll try to help people understand that. And we can also take a cut of the Phase III data at 14 to 16 weeks. So 12 and 16, I guess, we have the data point. So we'll try to frame it and again give people as much of an apples-to-apples as we can. The other difference in this trial is that it's 12 and above. So we don't have the 6 to 12. And if you go back to our original Phase II, we had several patients who are under 12 who did extraordinarily well in that first 16 weeks. They lost 30% plus. So our Phase II number was 14.5% in that Phase II trial. And it was driven disproportionately by, like I said, a few of these kids who are in the 30% range at that early time point. So anyway, these are the things that, again, small data sets. What we want to know is we want to know, do we have a drug. This is not -- we're not setting up a future label here. We're not -- we just want to know, do we have a drug, do we want to invest and go to Phase III. And I'm pretty hopeful that this trial will tell us. If it doesn't work, we'll know. I mean, no response is no response. Then we'll be done. But...

To your point, you've got a lot of data with setmelanotide, including in preclinical models. So as you look at what biva has shown, where you can look at apples-to-apples thus far, how did the 2 agents compare?

Yes. So I mean, and LG Chem, who we acquired the molecule from, as I've said many times, they did more preclinical work models than we've done. And we've repeated some of this now internally. You get identical results. Now the challenge there is, of course, it's a little hard. So when we do 718, our weekly, and the setmelanotide, those 2 molecules are very similar. And almost milligram to milligram, they're very similar. Whereas for biva, you've got a different molecule, oral route of administration. So you can get identical results. It's a little harder to take your preclinical dosing and extrapolate perfectly to your clinical setting. So people ask me, what -- how do you handicap all of these? I know both 718 and biva are very good MC4R agonist. All things being equal, they should work. I think the biggest variable, the unknown which introduces the uncertainty, is do we have the right dosing. And...

Sure. Okay. And maybe we can also go through some of the same questions on 718. You can talk about the study that's ongoing, the data later this year.

Yes. So we -- 718 weekly, as I said, very similar. It's a 7 amino acid cyclic peptide. Setmelanotide is 8 amino acid cyclic peptide. We built it off what we knew about setmelanotide. So a lot of reasons to feel good about the molecule itself. That -- we finished the SAD and MAD part of that. It's fine. We've got the PK we want. Safety is all acceptable, of course. And so we're getting that trial up and running. And what I've said and we -- still the goal is, it's an open-label study, to have something to say by the end of the year. I'm hedging now a little bit because we're definitely slower getting it up. It's just been hard at getting sites open again, and we can talk about that. But it's just -- but we're a little bit behind what we want to do. So we're just starting on the 718. But I'm still hopeful we can say something by the end of the year, but it may bleed into Q1.

Why has it been harder to get sites up and running? I mean, it's not your first rodeo, right?

It is not our first rodeo, but it is -- we've had challenges in the past getting -- and it's just, I can tell you, it's tough at these clinical sites.

Where is the break? Is it like getting IRB stuff? Or is it...

It's a mix of things. I mean, at the -- your key person in any clinical trial is your study coordinator. And so just depending on how many trials they're running, for better or worse, we're working with sites that are running more than one, just Rhythm stuff, of course. Contracting offices, they work at their own pace. You think in today's world with funding being what it is, they'd be thrilled to have a biopharma knocking on the door wanting to do stuff. But it doesn't translate. So those are the stuff. There's nothing unusual about it. It drives me crazy. But just it is what it is, and we're working on it.

So once you get the sites up and running, given your experience, how would you anticipate like patient enrollment? Is that -- do things smooth out at that point?

Yes, it should be good. And the other piece is we made it a little bit intense. We had a very intense pharmacokinetic requirement. So patients needed to be in the hospital with prolonged periods of multiple blood draws, and that's a problem. So we've now -- we're amending the trial to much lighten up on that dramatically.

Okay. One of the advantages of these programs from a Rhythm perspective is the patent. So could you just talk to us about the patent on the 2?

Yes. So incredible point. So let me just start with setmelanotide again because I want to make sure people understand that. So composition of matter for setmelanotide, 2032. What -- you've heard me now, let's talk about it a little bit more, what we hadn't so much in the beginning is our formulation patents for setmelanotide go out to 2034. When you get a drug approved, the FDA regulators put -- FDA specifically puts out a guidance document. Now going forward, that office has been -- we'll see what happens. But anyway, historically, they put out a guidance document that tells the generic what it would need to do to develop a drug for that. That guidance document basically takes you through our formulation patents. So we're feeling, in Rhythm's opinion, like, we may be in a reasonably good position there. So that would give us coverage to 2034. And the other thing that not everybody -- when they're modeling this, they tend to model end of composition of matter, whatever, with a cliff. And that doesn't happen in a rare disease world. And it doesn't happen because, a, the competitor, the generic entry tends not to compete on price because you can't make it up on volume so -- if you cut it. So they tend to price this similarly and then the companies compete for share, but -- and then the incumbent in that world has a pretty big advantage [indiscernible]. So we don't think in the setmelanotide world, there would be a cliff. Now back to the 2. Our new molecules are incredibly important because they both, with patent term extension, take us to 2040-plus.

Okay. Perfect. And then maybe like last question on the 2 endo franchise here. As you think about like the decisions you have to make around going forward, are they contingent at all on each other? Or will you make the decision...

Independently.

Great. That was the answer I expected. Okay. Maybe on other data this year. You've started to discuss a Phase II in Prader-Willi syndrome. Maybe like talk about the confidence, where you've got confidence in pursuing that indication knowing it's been something of a graveyard for drug development.

It has been a graveyard. I mean, it's just -- and we have tremendous respect for the challenges there. So as you know, we ran a trial in 2018, predated me. And that trial was negative. But quotes for everybody, it was complex and wrong design in the sense that it was earlier on in development so we were being, as a company, very careful on our dose escalation. The highest dose study was 2.5 mgs and it was for 4 and 8 weeks in a crossover design. So net-net, you could -- it was uninterpretable to me. We had a couple of placebo patients who lost a lot of weight. But if you look at the top dose, the 2.5 mgs in the patients who were on for 8 weeks, there was a response in a handful of patients, a small number. So not uninteresting. And as I said, from a trial design, you could say, "Well, it doesn't prove anything." And it doesn't prove anything. But there's hope. And then second, biologically, it makes sense. So the MAGEL2 gene is in the -- part of the chromosome that's deleted or imprinted here. And MAGEL2, we studied that gene and we studied it in our Phase II DAYBREAK study. In the 3 or so patients who we, based on their genetics, we knew that their variant was a loss of function variant, they had a good response. There's a mouse model. You knock it out. Mouse gets obese. You treat that mouse model with an MC4R agonist. They get better. So that biology is absolutely clear. It's absolutely present in Prader-Willi. And then the challenge of the disease is it's not just the hunger and the weight gain. It's the behaviors which are really challenging to deal with and a little bit independent. The hunger and hyperphagia may make the behaviors worse. But if you improve the hyperphagia, you don't necessarily make the behaviors better. So that's a big confounder. So what we're running now is an open-label trial with Dr. Miller at University of Florida. And we decided not to do a control. Lots of -- because there might be, "Well, you won't know anything without control." Actually, I think, conversely, you have to run a pretty big trial for that control group really to help you here. And the value of working with somebody like Dr. Miller, who just knows her patients extremely well, not all investigators know the patient the way she does, she takes care of them. And so I think working with her ability to interpret what we're seeing, I think our goal is we should come out of this with being pretty confident it works or it doesn't work. That's the belief and our hope. The bar here, arguably, is lower. Nothing has caused weight loss. Soleno get approved, but a reduction in hyperphagia, some behavioral improvements, but not weight loss. It's not totally clear how diazoxide [ works ]. It doesn't work through MC4R, so different pathway. So I think in a world where nothing has been able to show weight loss, if we can show 5% or greater weight loss, that's a drug and we would take that forward.

Okay. You're going up to the 5 mg dose with setmelanotide in this.

For 6 months, yes.

Yes. Maybe just talk about like where you've used 5 mg in patients before and how you think about like the safety and tolerability that you could see emerge at the higher dose.

Yes. In normal volunteers, we've gone to 7 mg. We did a 3-month study comparing our full setmelanotide weekly and a daily setmelanotide and went up to 5 mgs in that study. We have -- there's no, I think, safety issue. We have gone -- individually, there's been a handful of patients in our previous world, some Bardet Biedl patients, some patients in the original old Basket Study, who felt like they wanted -- felt needed more. And we've gone up to the 5 mg.

Are you allowing background diazoxide on the trial?

Yes, we are. And so there will be some patients there.

As you think about the next steps, if you see a signal with the open-label Phase II, do you move forward into Phase III from there? Do you wait until -- to see whether the oral or weekly? Like what are kind of the next steps in this patient population?

Yes. That's a really great important question. The answer is it depends. But it's shifted a little bit in our minds, my mind certainly. I think originally, and as we've said, we've been very clear that we do all our new development work with the next gen. Prader-Willi is unique and a big enough unmet need. If we see something that's meaningful there, by far, the fastest route of approval is with setmelanotide. It would be a supplemental NDA and we could move, in theory, pretty quickly. So that's the depends part. We'll see how the data looks. But if we are -- feel like it's making a meaningful difference, we'll go.

Okay. As you think about what a Phase III would have to look like, you obviously have done a couple of Phase IIIs in rare disease populations. You have the diazoxide trials to look at. Any key parameters you would anticipate being required for in the Phase III?

Everybody says the same thing. I mean, we'll use the HQ CT, which is -- monitors their hyperphagia and the like. So the tools that Soleno used, everybody uses. I mean, we'll for sure be incorporating those. As I said, we need to see changes on weight loss and so the traditional measures there with BMI. Body composition is really important. We haven't been as consistent getting that in some of our other trials. If we went forward, for sure, we'll be clear on that.

Okay. And then I guess, as you -- can you just give us a sizing of the addressable market and unmet needs in this patient population?

For Prader-Willi?

For Prader-Willi.

Yes. I mean, the numbers out there for the U.S. population, it's 10,000 to 20,000, so 15,000, whatever. I think, again, a very well diagnosed population. Part of the value that's been ascribed to Soleno in a very short period of time is that they're coming out with the first approval, which was really a huge step for the field, their ability to get approved there, but into a world where there's nothing.

Yes. Okay. You currently have said your cash runway is into 2027. So as you think about sources of capital and funding all of these potential programs, maybe first, what's included in that guidance? We've talked about a number of additional Phase IIIs. And how do you think about kind of sources of additional funding?

Yes. So we took some money down from the ATM, which allowed us to give new guidance into 2027. So that includes all of the existing clinical trials and our preparations for the HO launch. What's not in there is new clinical development work with the idea that if biva is positive, Phase III stuff is not in there for that, so -- which includes some investments in CMC. So there's things that, planning for success, arguably we would need to raise for. A big variable in that guidance is revenues and how well we do. I think Hunter and team have taken a conservative view of that. So we're not terribly aggressive in this guidance. But if we do better there than our needs, and as Hunter likes to say, we're solving -- we're not solving for a big number necessarily here. So -- and we have a number of different ways we could attack. And equity -- of course, stocks in a good position. We could do equity. But it ranges a full range. I mean, we've got a royalty with HealthCare Royalty Partners. And there, I think I've expressed a willingness in the past to be supportive of something else if we want to go there. And we're also maturing as a company, and debt becomes an option at some point.

Okay. In the final minute, I guess, anything else that you view as like significant value drivers that we can unlock with Rhythm over the next, let's call it, 12 to 24 months?

Yes. I think if people -- I mean, Rhythm is at a really exciting time and it's -- this pathway is fully validated now. MC4R path, I mean, in the beginning, it was just like, can you get your -- now it's like, okay, the drug is approved. You got a good MC4R agonist. Maybe you have some next-generation agonists as well. But this pathway, which historically always was viewed as important, I think it fell out of favor a little bit because people couldn't drug it. And now it's back in favor. And people are beginning to peel that onion and to say, okay, how many different "indications" might this pathway be important in? Because it's distinct. So you've got the Phase II DAYBREAK studies. You've got other causes of injury to the hypothalamus we've talked about. We talked about the congenital form, traumatic brain injury, which hopefully will be part of our current label and the indication. But the point being is I think there's a really rich area out there to be explored now that the pathway has been validated and we have a drug.

Perfect. That puts us perfectly at time. Thank you, David.

Thank you, Corinne.