Good morning, everyone. I'm Amir Fadia, Biotech Analyst here at Needham. I'm really excited to be hosting this panel discussion today on the Orexin 2 Receptor Agonist class because I believe it's going to be a significant advancement in treating excessive daytime sleepiness. It's my pleasure to be hosting Richard Pops, who's the Chairman and CEO of Alkermes, as well as Dr. John Carter, who is a sleep medicine specialist and the Medical Director of MetroHealth Medical Center in Cleveland. Welcome both to the panel. Thank you so much for taking the time to do this today. Thanks for having us. Thanks. Let me Thanks. Let me just, you know, kick us off with sort of a question, a fundamental question just around kind of the mechanism. Maybe, Rich, you can start us off here. The mechanistic rationale for this class is certainly well established in NT1, given the loss of orexin neurons in these patients. Perhaps to some extent, it is there even in NT2 because of the partial loss of orexins. The etiology is less known in IH. Yet, you know, we have seen data from Alkermes, which has demonstrated clinical benefit across all three types of patients. Perhaps if you could sort of elaborate on what you believe is driving that efficacy. First of all, it's great to be with you, Dr. Carter, and with Amir. It's interesting. This biology is relatively new. I think the first papers were 1999, 2000, elaborating the hypercretin orexin pathway and its effect on wakefulness. Nature has provided us the knockout model, which is orexin, I mean, in narcolepsy type 1, which is a deficiency of this bundle of neurons. As you say, if you drew concentric circles of the potential utilization of an orexin 2 receptor agonist, the core of it is it would be in NT1, where we have a paucity or an absence of the neuropeptide. We and others have shown by replacing that neuropeptide with a small molecule agonist, you can essentially replicate what the neuropeptide does and significantly address the excessive daytime sleepiness associated with it. One would hypothesize then that it might also work in NT2, IH, and even in healthy brain or non-orexin deficient brain based on a couple of things. Number one is what you said, the empirical evidence now. We actually have data from I-B study showing in a dose-dependent fashion, we can improve wakefulness in this patient population. That's probably the most powerful information. Remember, even early in our development, looking at healthy volunteers non-sleep deprived, we saw changes in quantitative EEG measures consistent with the idea of wakefulness and vigilance and attention. I think all that adds together. I think that the proof point will be what we're doing right now, which is a proper phase II study, 80 patients in NT2, 80 patients in IH, a range of doses over a multi-week outpatient setting. We all can sit down and look at those data and say, okay, what's the real phenomenon that we're realizing with the use of these drugs? Yeah, that makes sense. Dr. Carter, anything you'd like to add? Any open questions from your perspective? I think you've hit upon a key question sort of driving at the underlying physiology and mechanism here. It's certainly one that on the clinical end, we share. I tend to agree with Richard that there is growing evidence for the role of orexin agonists even outside of the quintessential case, which is narcolepsy type 1. You know, in my mind, wakefulness is a spectrum. It's not an on-off switch. It may be a matter of replacing lost function in NT1, but outside of that, whether it's NT2, IH, or even other conditions, you can still turn up the volume on alertness through orexin neurobiology. I suspect in large part that's the mechanism that is being tapped into. Okay. I wanted to talk about what this class, you know, can offer to patients. Perhaps just for context, Dr. Carter. I hate to interrupt, but I'm glad you're interrupting. I think what Dr. Carter just said is so important. I think for many people new to the field, we tend to focus on the quantitative measure of wakefulness as evidenced in the Maintenance of Wakefulness Test that we're using in the NT1 study, i.e., how many minutes one stays awake in a dark, quiet room. That is a measure of something, but it's not a measure of the overall phenomenon of being awake and conscious. Our belief is this orexin system does more than keep you awake in a dark room. It impacts domains associated with mood, vigilance, attention, all these other things. What's so exciting about this being a new field of research is that I'm highly convinced that 10 years from now, we'll look back and have a much more nuanced, multidimensional understanding of what this circuitry does in the brain. Yeah. No, I think that's a great point. Okay. I wanted to just sort of put in context what this class can offer in terms of efficacy. And so maybe just if I could ask Dr. Carter to sort of characterize what current therapies offer in terms of efficacy benefit. The overarching message to deliver about narcolepsy and other hypersomnia therapies is that there is very significant unmet need. Although many people with narcolepsy and other hypersomnias experience significant improvement with other therapies, many of them require multiple prescription drugs in order to do that. There are still significant gaps, particularly in NT1 and IH, but also in narcolepsy type 2. To kind of echo Richard's point, we certainly have drugs that can target alertness, stimulants, and things of that nature. We are very much in the infancy of understanding the full spectrum of what the real need is in narcolepsy. A phrase that I've heard from a couple of my patients now has really stuck with me is that, you know, these drugs help me feel stimulated, but not awake. That is a relatively common experience in this patient population. You know, we do have a number of therapies, including the old school stimulants, which have some benefit, somewhat newer wakefulness promoting agents, and newer medications that work through a variety of mechanisms such as the oxybates, pitolisant, solriamfetol, et cetera. The paradigm currently with narcolepsy is very much one of polypharmacy. Not for every patient, but for many patients. It is one of polypharmacy and significant unmet need. Yeah. So Richard, as you've been developing this class, you know, what is sort of the end goal in terms of the target product profile, at least for kind of your lead compound here in terms of what you're looking to achieve in terms of efficacy? I think drug development is about trying to harness efficacy within the context of a tolerability profile that's acceptable to the patient from a risk-benefit perspective. All medicines have side effects. A lot of the work we do in phase II is to try to tune and find that dose that is the right balance between safety and efficacy. Categorically, you'd say that this category so far has shown remarkable tolerability. The side effects that we and others have demonstrated so far that are on target tend to be mild to moderate and transient. They actually attenuate with time in the one eight-week study that we have data from. The target product profile is to deliver best in class, in fact, new domains of wakefulness from the existing medications. I think Dr. Carter can comment on that. I mean, we know what oxybates, we know what stimulants will do in the MWT, for example, which can take single-digit latencies and make them, you know, low double-digit latencies. Whereas the orexins have shown the ability to, at doses, max out the 40-minute test for many, many hours. It's not shades of the same color. It's a profound different level of wakefulness. As one of our thought leaders said, you know, if we drove this much wakefulness in the MWT with stimulants, the patients would be psychotic. It is a really different opportunity for patients to achieve levels of wakefulness that were here before unachievable. If we can do that with a side effect profile that's mild to moderate, transient, and doesn't lead to discontinuations, I think we've made a big advancement for patients. Yeah. You know, as we think about sort of the data that's been generated and, you know, sort of going back to that mechanistic rationale and taking kind of these studies that are smaller in size to help you identify the right dose and the proof of concept, and thinking about kind of the larger studies, which would be more sort of registrational, particularly, you know, I think investors want to better understand how to think about NT2 and IH as indications where, you know, do you think we can replicate, we can see replication of the profile that was seen, particularly for, you know, ALKS 2680 in kind of that larger eight-week treatment duration? Yeah, we don't see any reason a priori why you would expect tachyphylaxis or any phenomenon different than we saw in I-B, but that's why you do the experiment. That's exactly how science works. We have data from a crossover design where we tested multiple doses and one dose in an intense inpatient setting to really understand target engagement, dose response in order to inform phase II. In phase II, we enroll 80 patients. What's interesting, if you sort of drew a histogram of the clinical presentation of an NT1 patient, it's a more monodispersed figure. NT2 and IH, it's much broader. Phenotype is much more. Variability is going to be a big issue. If you saw the presentation we gave at our investor day, for example, we talked a lot about how we model and incorporate variability into our modeling for dosing decisions. What informs that model, what populates the model is actually data from patients. In the 80 patients that we're going to get now, we'll have a whole range of clinical presentations, and we'll be able to map on the responses and do more modeling to decide what do we do in phase III. Operationally, the phase III looks just like the phase II. I mean, it's just, we're not really powering these things so much for efficacy in NT1. The effect size is so large. It's really to establish that tolerability dose profile that we can take into later studies. Yes. I think Dr. Carter earlier talked about the polypharmacy sort of is the way that patients are being treated today. Where do we want to get these patients to ideally, whether it's with one or multiple drugs? Maybe Dr. Carter, from your perspective, what is sort of the gold standard or what is the target as to where you want your patients to get to with appropriate treatment? With the caveat that the MWT is a very sort of monodimensional measurement, the absolute maximum would be 40, four-zero minutes. Generally, a latency above 20 minutes is considered to be the normal range, so between 20 and 40. My general conception of what I would shoot for in terms of an ideal result would be somewhere in the 25-35 minute range. Every patient is different, obviously, but I mean, to use a very simple example, if you have a 30-minute commute and your mean sleep latency is 25 minutes, that's a failure for you. We may not be trying to max out the MWT, but certainly more is better in the vast majority of cases. You know, as we sort of think about what is ideal and, you know, as sort of you think about multiple treatment options down the line, and there probably will be several, is more always better for everybody, or do you just need to bring them to the normalized range of, you know, over 20 or 25? I think it's a very, very important question. As a general rule, more is better. As we start to hit the 40, sort of let's say 35-40 minute zone, that allows us the freedom to start looking at important other variables, secondary outcome measures. You know, I'm very confident we are going to reach a point very soon with the orexin agonist class where every molecule coming to market is easily able to achieve these very robust results with MWT. The differentiation then comes in A, tolerability profile, B, dosing regimen, which does matter to patients, once daily, twice daily, et cetera. C, what other benefits does it afford? What does it do for cognition and memory and mood, all of which are wrapped up in attention and alertness, but not really captured in the MWT. Those, I think, are critically important things to look at. To answer your question very simply, you know, am I inherently worried about a patient with a 40-minute sleep latency on the MWT? No, I'm not, unless that 40-minute latency is also accompanied by very significant insomnia. That's the balance, I think, that needs to be struck. I mean, can I add two points to what Dr. Carter just said? Please. Number one is that our view is that we want to test that empirically. In our phase II study, for example, there is a six-week double-blind period where people stay in their dose lane that they have been randomized to. At the completion of the six-week period, all patients in open-label fashion go to the middle dose of the three doses for two weeks, and then they get to choose whether they go up or down. This will be really interesting to see whether some people want more wakefulness or less wakefulness. Is there too much? Is it too little? That real-world experience is going to be important. A. B, as we move from NT1 into NT2 and IH, given the range of clinical presentations, it stands to reason for us that there might be a range of doses that are necessary. A patient with an NT2 presentation looks more like an NT1 patient might need a different dose. They might be more responsive to orexin agonist than one that has a 30-minute latency. We'll learn this also empirically in the conduct of phase II clinical trials. Maybe a related question for Dr. Carter. Do you think that there's value in that type of flexibility as you think about treating patients down the line? There certainly seems to be a lot of heterogeneity, especially in NT2 and IH, as Rich pointed out. I would imagine that you would want that type of flexibility. I absolutely agree with that. I mean, in addition to the variability that we see sort of across the cohorts of NT1 versus NT2 and IH, with NT1 being in general much more homogenous, NT2 and IH in general being much more heterogeneous, there's also significant inter-individual variability. You know, not everyone is experiencing the same side effects, the same symptoms. Not everyone needs the same dosing regimen, strength, et cetera. Very, very simple example. I mean, we see essentially no agreement among our patients with narcolepsy regarding whether once or twice daily dosing is better. Some people prefer the flexibility of twice daily dosing. Other people understandably prefer the ease and simplicity of once daily dosing. At least in my practice, it's an even split right down the middle. To your point, having flexibility and options, both in dosing and also the timing regime, is really, really critical to treating patients in the real world. Our view on that, Ami, on the once versus twice daily data, again, goes back to the data. The theory, when you need twice daily dosing, two things happening. It implies that there's a tail, a backside of the efficacy that needs to be bolstered again. That means there's a period of time where you're not achieving everything you want from the drug, perhaps. Also, you're subjected to two peaks, two Cmax peaks. To the extent that there are AEs associated with either rate of change or absolute peaks, that would be duplicated on a daily basis. Those will come through in the data. That's theory until we do the experiment. Also, isn't there some type of, you know, lack of compliance from patients with regards to exactly what time in the day they take that second dose? Is that something, you know, to be worried about? It's a real phenomenon. I would say the negative side of that is missed doses and mistimed doses. If you take it too late, it results in insomnia, that kind of a thing. On the other hand, it is sometimes the case that patients prefer the flexibility of taking the second dose. Again, if you're limited to one dose during the day and it works well for you, great. If it's wearing off too early, you're out of luck. I certainly agree with Richard's comments about the AEs inherent in dual peaks and so on, and that point is well taken. I will say the feedback we hear from the narcolepsy patient community really does sort of split down the middle. There's very clearly a convenience argument to be made for once daily, possibly a side effect as well, though some patients do feel fairly strongly that they want the control and flexibility of more frequent dosing. Not many. It's a minority, but it's a sizable minority. Dr. Carter, we're also doing the experiment probably with the oxybates, right? You would think that perhaps once a night oxybate is better, but some people prefer twice a night oxybate. Exactly. Yeah, exactly. We've seen a real-world example of that. Okay, great. I kind of want to just step back and maybe ask a question that maybe, you know, both of you can answer. You know, Dr. Carter, as a physician, you know, based on the data that we know, and you know, I want to dwell a little bit more on the safety comparisons a little bit later, but just purely on efficacy, do you think that there is a discernible difference across at least the three companies that are leading in the space, you know, Takeda, Alkermes, and Centessa? Do we know enough about the data? Of course, we have different levels of data from all three, so acknowledging that. How are you going to think about differentiation across the three? Focusing only on efficacy and taking into account all the caveats that you mentioned, my impression is that there is a signal towards more robust efficacy in the ALKS 2680 product and possibly in Centessa's product with the caveat that, again, we're only basing that on healthy sleep deprived volunteers. A couple of reasons I say that. One, yes, there might be small differences in the absolute value on the MWT, but also the condition in which the medication is being applied and studied matters a lot. You know, as we open the conversation with, I think we've all expected for 15 years, 20 years that narcolepsy type 1 is going to respond very well to orexin agonists. It is a much more recent development and a pleasant surprise that that is also true outside of the orexin deficient states. However, it seems to be the case that higher doses expectedly are going to be required in NT2, in IH, in other words, outside of the orexin deficient states. The big question, you know, for me with the data is, are we still able to achieve meaningful and robust clinical efficacy in those non-orexin deficient states? Again, acknowledging all the caveats and limitations of the data, the answer to that seems to be yes with a stronger signal for the Alkermes and Centessa products, in my opinion. Okay. Maybe, Richard, would you like to sort of comment on that? You know, I think the one thing is we do have different levels of data, right, from the different companies. Maybe one thing I would like to better understand is how do we look at the healthy volunteer data from, you know, any of these drugs and think about translating that? Perhaps, Richard, if you could talk to at least, you know, how you guys thought about your development program in that regard. Dr. Carter, how do you sort of view that data? Yeah, I'll give you our perspective on the relative state of the maturation of the data. Takeda has the most mature data because they have eight-week data in the outpatient setting at an efficacious dose to interrogate safety and efficacy and tolerability. We have patient data of a significant cohort in NT1, NT2, and IH showing consistent dose-dependent responses on the measures that we tested. We're the only ones who have patient data. What we found is that in our work, we couldn't recapitulate the sleep pressure that you would find in a narcolepsy patient in a sleep-deprived healthy volunteer, particularly if you only keep them up until 11 or 12 at night. It's a setting for testing target engagement, perhaps, but our sense was you need to be in the patient population of interest to get a sense of dose and tolerability at that dose. We expect actually a shifting dose response curve as you move from NT1 to NT2 to healthy volunteers, both in terms of efficacy as well as tolerability. The setting to establish dosimetry and tolerability and efficacy profiles is in that patient population. I think that that's not saying who's better than that. It's just an acknowledgment of the state of development of each of the various programs. Yeah. Maybe, Dr. Carter, could you sort of just comment on kind of how you see that? You know, we earlier talked about just bringing patients to a kind of a normalized level, and you acknowledged that, yes, you'd take 40 if you, you know, have that. You know, as we evaluate multiple products, you know, as analysts and investors that cover these companies, how many points of difference in MWT really matters? Is it just about bringing somebody to a normalized level? If we see, I don't know, 32 versus 35, is that meaningful difference? Maybe if you could comment on that. Sure. Two parts to that question. The first part, I think, was sort of around how do you interpret or translate healthy volunteer data into the patient population. I, you know, I think certainly healthy volunteers are going to need a higher dose compared to somebody with NT1 and probably NT2. Assuming that there's a dose response between dose and efficacy and also dose and adverse events, I think you're probably looking at something like an NT2 and IH profile in the healthy volunteer data. That's a very rough sort of rule of thumb type assumption. In other words, the doses that normalized wakefulness in the sleep-deprived healthy volunteers are likely above the doses that will be required for efficacy in NT1. That's sort of my view on things. That, again, acknowledges very significant differences in the underlying physiology. We're not just dealing with sleep-deprived people. We have a dysfunctional, very broad cortical network that's tied up in orexin deficiency. I have to add that caveat in there. To answer the second part of the question, what is a meaningful change on the MWT? There is, I would say, more art than science here. You know, my general view is that certainly bringing someone from abnormal into the normal range is clinically meaningful. If someone is near the normal range, generally, I consider a 10-15 minute increase from baseline to be clinically significant and meaningful. Again, the data we have across this asset class seem to back that up. I guess I would also point out, although we could all look at these, sort of the maximum dose studied in each of these trials and the MWT result associated with that, in clinical practice, you know, it's going to be very useful for me to have dosing options. You know, I want a low dose, a medium dose, and a high dose because not everybody needs the high dose. Not everybody wants the high dose. We want the ability to tailor the degree of clinical response and the duration of clinical response to what the patient actually needs. For me, yes, I love to see those high bars above 25-35 minutes, but it's also very important to see that dose response in a linear fashion. Yep. Okay. That makes a lot of sense. Just beyond MWT, which we've sort of talked about quite a bit, what are some of the other endpoints that are worth studying or which, you know, you guys are sort of thinking about evaluating? You know, is there going to be a difference in the rate of response across these treatments? What is the rate of response currently to, you know, ALKS 2680? I don't know if that data is out there. I'm just curious how that will come into the mix of things. I think NT1, the coin of the realm, would be MWT, Epworth, and cataplexy rates. Those are all three being tested in trial. In NT2, we use the MWT in Epworth. In IH, we do not use MWT. We use the idiopathic hypersomnia scale in Epworth. I'm particularly interested in Epworth. I'm curious what Dr. Carter says about it because unlike the MWT, which has the virtue of being an objective measurement that you can do math around, Epworth tells patients they tell physicians how they feel. Even though it's a blunt instrument, it's an important instrument because we could probably keep you up for a long time in the MWT study in a condition you would not enjoy being in. The Epworth captures then the feeling of being on the medicine. I think that in phase III, I mean, we'll use all three of those measures, but what we're doing in phase II is we're interrogating a whole range of patient-reported outcomes to try to see where we detect signal. If it turns out to be an instrument that we and physicians like Dr. Carter think are relevant, we want to incorporate that into our phase III program as well. I certainly agree with that sentiment. I mean, the value of combining MWT and the Epworth Sleepiness Scale is that we're getting multiple lines of information, one of which is subjective with some bias, obviously, the other of which is objective. The other thing, of course, is that in clinical practice, you know, we don't have readily available MWTs to do on command. We rely on instruments that we can deploy in the clinic in a couple of minutes or even remotely. There are a number of subjectively rated sleepiness screening instruments, the Stanford Sleepiness Scale, Karolinska Scale, et cetera, et cetera, the Epworth, obviously. I think all of which capture something important and subjective and meaningful to the patient. I would just follow that on with one other sort of comment. Totally agree. You know, at this stage of where we're at with orexin agonists coming down the pipeline, MWT, Epworth, cataplexy rate, et cetera, are all the key primary measures to look at. Things that I'm excited about seeing response rates for have to do with those sort of ancillary measures of alertness and attention, psychomotor vigilance, memory, mood, et cetera. Particularly, you know, looking down the road three, five years when we have three, four, or more orexin agonists sort of playing in the sandbox, all of which are maxing out objective measures of sleepiness, all of which are reasonably well tolerated at the most common doses. The things that I'm going to be looking at in terms of, you know, which one do I prescribe to this patient versus this patient is, you know, what else can I get you? What other benefits can I offer in terms of your daytime function? It's a bit of an open question, at least in my mind, about whether those sorts of things are class effects. In other words, will all orexin agonists improve the attention network because that's just what they do? Or will we see molecule-specific differences among those? Not to hedge too much, but I suspect it's a little column A, a little column B, right? Certainly, we will see some class-specific improvements across those measures, but I would be very interested to see molecule-specific differentiating factors in those secondary outcome measures, you know, over the next several years. Maybe build on that, Ami, because it's a critical point. Think about it. There are two dimensions to that. One, are there intrinsic molecular differences that drive different behavioral responses or cognitive responses? You have to test them. The companies that actually do the work, spend the money, invest in the research, will have that dataset to be able to share with clinicians and patients. If you do not do it, I do not think you can just ride on the coattails of people that preceded you. I think there is a real virtue to being early and pioneering in articulating and identifying some of these differences. Yeah. Okay. I wanted to sort of hone in on the safety profile of this class a little bit. I think previously, Dr. Carter talked about some of the limitations of the current treatment options in terms of just their tolerability. Perhaps without dwelling upon that, maybe let me ask Rich, you know, some areas of interest have certainly come up with this class, you know, insomnia, polyuria, visual disturbances, urinary urgency, so on and so forth. As a drug developer, you know, as you've thought about kind of balancing that risk-benefit profile, what do you view as what would be acceptable in terms of the doses that you've picked across the three indications? I think the profile remains the way it looks like it is established in the Takeda eight-week study and what we've seen early in our phase I-B study. I think that would be a very attractive profile. As I said, mild to moderate transient phenomena. The on-target phenomena we know that we can say reliably now would be insomnia, which tends to attenuate over time, and polyuria, this urinary urgency also, which tends to, based on the Takeda data, attenuate over time. What was notable from our perspective, and we really give a lot of credit to Takeda for being so forthcoming with the presentation of their data, is that we saw really no patient discontinuations based on those adverse events. Also in the patient-reported outcomes, a very, very high level of satisfaction with the treatment. To the extent that these mild-moderate side effects are manifesting themselves, they seem to be overwhelmed by the quality efficacy that patients are getting. Yeah. Dr. Carter, you mentioned earlier in our discussion that, you know, it seems that many of these drugs will bring patients to that normalized level of MWT. And perhaps there is going to be some potential for differentiation on, you know, other aspects of efficacy that you just pointed out, but also safety. Are we seeing a difference in safety across the different products at this stage? My interpretation of the available data is that there's not major signal in terms of differential AE rates, with one important caveat that with the higher doses used in NT2 and IH, again, we could reasonably expect a higher adverse event rate. Doesn't really seem to be spiking. There is possibly a ceiling there. You know, with the data we have from Takeda, that's obviously moving forward only in NT1. They're limiting the dose as a result of that. With that caveat in mind, I tend to conceive of all three of these products, Takeda's, Alkermes', and Centessa's product as generally in the same ballpark in terms of adverse events. I would agree that what we've seen reported looks to be on target. There's some important granularity that I would like to see, particularly around visual disturbances, which I suspect is probably just to do with, you know, the pupillary light response as opposed to something more concerning like visual hallucinations, although again, granularity is important there. My sense from the data is that we are at a point, as Richard brought up earlier, where the sort of needle has been threaded between a high level of clinical efficacy and also a favorable tolerability profile. You know, the sort of safety signals that emerged with some earlier Takeda products, 994, et cetera, I think are sorted out at this point. I do think things like the duration of side effects and obviously their severity may be an important differentiating factor for patients and for prescribers like myself, especially in those groups that are likely to require the higher doses, again, NT2 and IH. This is from our perspective. I think this is also where if you stipulate that there's a certain on-target inherent set of AEs that might derive from orexin 2 receptor agonism, the space between various molecules could be defined by potency and PK. That, again, we'll learn in the clinic. Yeah. I suppose one additional follow-on point is that obviously everybody is very happy when the AE profile is minimized, but looking at the selection of available medications that we have to us presently, we are very used to significant side effects, particularly with the stimulants and particularly with the oxybates. I mean, these are reasonably effective medications, but again, with significant adverse events attendant to them and potentially even some safety issues. I mean, oxybates can be deadly in overdose. Big picture, at least per my reading of the data, I mean, not only do the orexin agonists appear to have an acceptable AE profile, but I would say it's even favorable compared to what we have presently available. Right. The mild to moderate AEs that occur in the initial period of the treatment is still a welcome improvement over what the patients have currently. That's right. Okay. Perfect. I want to move on to market dynamics. Obviously, you know, the number of patients across these three indications that suffer is large, and a lot of them get treated with antidepressants, stimulants, et cetera, and maybe a smaller portion are being treated with the oxybate class or Wakix and Sunosi, as you mentioned. How do you see this new class impacting, you know, the% of patients that get treated with this new class, and is that going to vary across NT1 versus 2 and IH? Dr. Carter, you can go with that. Rich, if you want to chime in. Sure. At the risk of sounding hyperbolic, my impression of the orexin agonists is that they will be quite literally transformative of the treatment landscape. Certainly not 100% of patients will be, you know, ultimately on these medications, but I'll give you an anecdote. I mean, narcolepsy patients as a rule tend to be highly engaged. There is very strong community advocacy, very strong interest in what's going on in the research world. We as clinicians not uncommonly hear about new pipeline therapies from our patients. I can tell you certainly the buzz among the patient population for orexin agonists is strong and has been for quite some time. I'm certainly discussing orexin agonists with 100% of my patients with narcolepsy and a large fraction of my patients with IH. Reading the tea leaves a little bit, I think another important dynamic, which we touched on earlier, is for some patients, I anticipate that we'll see a transformation from a polypharmacy regime to a monotherapy regime. And that's advantageous for lots and lots of reasons. Fewer side effects, better tolerability, better safety, lower costs, better convenience. I mean, it's really sort of better across the board, and there's strong patient interest in that. If we wanted to get sort of quantitative, you know, when I've looked at my own practice at sort of a mature steady state, it wouldn't surprise me if a majority, 55-60% of my patients with NT1 ended up on an orexin agonist of one sort or another. That's going to take some time, obviously, but I think that's steady state. I'd anticipate that would be a bit lower in NT2, maybe 35-40%, simply because of the higher required doses and the somewhat lower unmet need in NT2 compared to NT1. Interestingly, I might anticipate 50-60% of my IH patients ending up on an orexin agonist. The reason for that has everything to do with the unmet need. These are patients who, again, in general, tend to require lots and lots of medications and very high doses of them. You know, doses of stimulants that make me nervous, to be quite frank. Any opportunity to reduce the doses of other therapies, to condense modes of therapy from polypharmacy to monotherapy is a big win in IH. Again, at the risk of sounding hyperbolic, I anticipate pretty significant uptake in my patient population. Richard, anything to add? I do have a follow-up for Dr. Carter. Quickly, I do. And you know, we do extensive market research, but we do it by talking to experts like Dr. Carter. So everything he said is consistent with what we're hearing in the population. The additional that I'll make, I'm curious for Dr. Carter's response to this, is that the actual prevalence of narcolepsy is on the order of 200,000 patients in the U.S., 100,000 of which are diagnosed and 80,000 of which are treated. And our thesis is the disparity between the prevalence and the treatment is because of a lack of awareness of primary care. I mean, we're talking to Dr. Carter, a prominent sleep specialist. That's a rarity in the community. As safe and effective medications become available and we start investing in disease awareness and teaching at the primary care level, I can see that number converging. Because we hear about patient journeys that can take 10 years before people finally get the definitive diagnosis. If we can shrink that down for patients, we could help a lot of people. Unfortunately, I'm forced to agree. That's all very true. I would just add briefly, I mean, even within the sleep medicine community, we see barriers, not so much to diagnosis, but to treatment among sleep physicians, simply because some of these medications are quite onerous to prescribe and monitor. They have real safety concerns. They're all controlled substances with one or two exceptions, which have their own sort of complications associated with them. Anytime we simplify the regimen, and we've seen this in other sleep disorders, sleep apnea, et cetera, but as a rule, I mean, anytime you simplify the regimen, you open it up to more people, and that does drive up appropriate diagnosis rates. Before I ask you a question about polypharmacy, just with regards to the 35-40% you mentioned for NT2, while they are higher doses, if they're still within that similar safety profile as what gets offered to NT1, wouldn't more patients that are NT2 patients want to try it? Or do you think they're just not as sleepy and they just don't have as much of an unmet need? It's the latter. You know, obviously every case is different, but there are, you know, more patients with NT2 compared to NT1 who are actually getting through life just fine on a single agent. Sometimes the devil's in the details, and we found if you really start drilling down and asking about, well, how do you function in this scenario, this scenario, this scenario, that the unmet need appears greater than it did initially. There is some work on the clinical end to uncovering the true need. In general, many patients with NT2 are less sleepy, less severely sleepy compared to their compatriots with NT1. Just with regards to the potential to eliminate polypharmacy, I guess if a patient is able to get back to a normalized state, wouldn't, you know, sort of basically half the patient population across the board, roughly speaking, just no longer need a second treatment? Is it as simple as that? You know, the question that is top of mind for a lot of people who sort of think about the oxybate market is, is this going to be a huge impact to, you know, oxybates and other drugs like Wakix and Sunosi? You bring up an important point, and I think the crux of that answer depends on what else are we targeting in terms of our treatment, what other symptoms are our patients experiencing. If we're treating only MWT, then that argument is absolutely correct. The reality is, you know, as we've been discussing, the symptom profile is really multifaceted. Regarding the oxybates in particular, I mean, my sense is that many patients with narcolepsy and IH will be excited to transition from an oxybate to an orexin agonist, but not all. One of the big unanswered questions in my book is to what extent, if at all, will orexin agonists benefit nighttime sleep? There's some reason to believe that they won't. You know, Takeda has given us some very limited data in abstract form a few months ago. Mechanistically, you know, orexin levels fall to very low levels at night in normal physiology. You could make a convincing argument that boosting orexin or agonizing orexin during the day is not likely to have much impact on nighttime sleep. To echo one of Richard's earlier points, we don't know unless we know. We don't know unless it's studied. I am very, very interested to see more data on what actually is the impact on overnight sleep with orexin agonists. If the answer continues to be minimal, then medications like the oxybates will probably continue to have a role. This is off-label currently. We all know they benefit nighttime sleep quality, though they can't be marketed for that, though we may see manufacturers seeking a label for that indication. On the other hand, if orexin agonists do have a real benefit on overnight sleep quality, reducing sleep fragmentation, reducing REM sleep instability that's inherent to narcolepsy, that's a different story than that really does put a dent in the oxybates in a more significant way. Richard, I'm sure you have thoughts to share on how you guys have thought about developing 2680 on this. I think we have a chance of making a real contribution to the whole field in these phase II data because for the first time, we can test a range of doses to explore the whole dose response curve as it relates to sleep architecture. You know, Takeda showed some data at one dose last fall, and it was provocative, but incomplete. We will be able to ask that question because within our six-week double-blind period, all patients will have a night overnight, and we will do PSG, and we will be able to look at sleep architecture in a dose-dependent fashion. I think then we will all know a lot more about what it does to sleep architecture. Of course, the theory is that if you consolidate wakefulness into a big block during the day, you should correspondingly consolidate your sleep in a similar way. That is theory. We'll see whether that's the case. I think the critical point to realize for investors is that, unfortunately or fortunately, the oxybates are not the entrenched standard of care that must be displaced by a new agent. Of the 80,000 patients that are being treated, about 16,000 are on oxybates. What's interesting is a lot of patients have tried them. Because it's worth a shot and because the disease, it's such a devastating disease from day-to-day lifestyle for people that are willing to try it, most of them don't stick with it for a lot of reasons Dr. Carter mentioned. I think that there may always be a dedicated cadre of people who love what they do for them at night. That's fine. I want to tie a lot of the, you know, great discussion that we've had and maybe just ask this question of maybe Dr. Carter. There are multiple variables to think about, right? Takeda is probably going to be first to market on NT1 and is probably looking to a follow-on product for the other indications. Alkermes has the biggest breadth of data and probably will launch NT1, NT2 around the same time soon to follow with IH. We also have Centessa sort of making progress on all these three indications. You know, we talked about differences in dosing. We talked about different options with regards to kind of the doses that will be available to physicians. How does all of this translate into which product or which products may have the best shot at the biggest market share? A couple of important variables to consider. One that really isn't trivial is which addressable diagnosis are we dealing with? I mean, narcolepsy type 1 is one-third approximately of the total narcolepsy population, whereas NT2 is two-thirds. Any agent that's addressing only one-third of the market is inherently addressing a minority. As we see more and more products that address the range of conditions, that's an important thing to consider. You know, at the risk of giving you a non-answer, it really is about the balance, right? Narcolepsy treatment is highly individualized. What's important to me when I'm thinking about which medication to prescribe to a patient is how can I line up my therapy to best eliminate their symptoms? You know, are they having day-long symptoms? Are they having peaks of symptoms? Are they having mostly nighttime versus daytime symptoms, et cetera? Having a wide armamentarium of medications in terms of their peak efficacy, in terms of their PK, in terms of their tolerability profile is really important to me. The short answer is a diversity of options really matters when I'm selecting among them. If you hold all those things equal, the, you know, the robustly efficacious medication with, you know, a reasonable tolerability profile and ease of administration is probably going to be my first pick. Okay. Richard, I don't know if you have anything to add here, but please do. We are kind of running out of time, so I do want to also touch upon just what are you thinking more broadly beyond 2680? You've sort of talked briefly about exploring opportunities in other indications beyond the three that we've talked about. How are you approaching that? What will be important to think about as you develop beyond that? The way that we're operating right now as a company is almost presupposing that we have a drug for narcolepsy. I don't mean to be, you know, overly ambitious, just operationally, you know, that's what you have to do. We're building a factory. We're laying in the supply chain. We're scaling up API because we think that that signal that we've seen in narcolepsy should endure and mature. If you think about it that way, if we're seeing effect in some of these concentric shells that aren't driven entirely by orexin deficiency, the probability of this pharmacology extending to indications beyond excessive daytime sleeping is actually quite high. We have shown some data that you have seen us present in animal models looking at attention, for example, and mood, and how this bundle of neurons that originates in the hypothalamus extends into areas of the brain and drives prefrontal cortical serotonin or norepinephrine, for example. There are ways of looking under the lit lamppost that we think that these agents will affect other conditions. It starts with establishing the safety and tolerability within the most, you know, intense setting and the most risk-benefit advantageous setting. If we see efficacious benefit and tolerability in NT1, NT2, and IH, we are going to continue. We are actually putting two additional molecules into the clinic this year in anticipation of expanding the program in that way. Okay. Unfortunately, I'm being told that we are out of time, and so I will have to close the session here. I really enjoyed the discussion with both of you. Thank you so much for your time and your very interesting thoughts here. Thanks to all our listeners for joining. Thank you.