All right. Good. Okay. Thank you. Welcome to our next session. We are lucky enough to have Alkermes. We have Richard Pops, who is the CEO. We have Blair Jackson, who is the COO. Thank you very much for both joining us. Rich, I'll give you a chance to kind of make some opening comments. I thought after that, we'd kind of hit some of the growth drivers for the base business and then move into the orexin franchise, which I think is where everybody wants to kind of hear you talk. You know, I'll throw it over to you. Recognizing that, I'll be brief. Thanks for having us, Mark. It's good to see you. Part of the most reductive way to explain where we are right now is that we have brewing one of the more interesting pipelines in the biopharmaceutical space now. It's not just our opinion. It's credentialed by other players as well. That's this orexin 2 receptor agonism space, which relates directly to the treatment of narcolepsy. The penumbra around it is quite vast. I think of the narcolepsy indication as the proof point of the circuitry in the brain and the pharmacology. Success there almost dictates expanding into broader indications that relate to mood, attention, vigilance, things like that. Because we are advantaged by having a billion-dollar top-line business of commercial products that generate significant profitability, in effect, that R&D is defeased. I mean, we have a self-funding approach to what we think is going to be a very large, a large new market. From time to time in biotech, new white space opens up as new categories are discovered and exploited and credentialed. They often lead to very long-term value creation in new spaces. Hopefully, that's what we're right on the threshold of. Importantly, in that construct, this year is the year because we're going to have 160 patients' worth of data in a very rigorous phase II design in NT1 and NT2, the principal forms of narcolepsy, which will provide a significant increment of new information to the entire field. Because for the first time, you'll see data in NT1, NT2, a range of doses with a once-a-day drug in the outpatient setting for six or eight weeks, double-blind, followed by seven weeks of open label. We'll get a really clear picture of the efficacy, the tolerability, and the overall safety and the patient preference for these medicines. I think with those data in hand, we and others and all of you will have the ability to make a real assessment of the medical and commercial potential of these drugs. The base business that we have, and we'll talk about it, Mark, is also remarkably, I think it's distinctive. We're really proud of it because we've learned how to sell drugs in very difficult markets. We sell drugs for the treatment of addiction and serious mental illness, long-acting injectable and oral, in places where the government is the primary payer. The patients are disadvantaged and stigmatized. The gross nets are very high. Access is extremely limited. There's generics that are put in front of you, all kinds of reasons that make it difficult. We figured out and created a commercial configuration that can play and thrive in this type of environment. Ideally, we would love to build on that and put more products into that infrastructure, even while we exploit this opportunity in the more specialized neurology space in narcolepsy. That is what we like about the sort of the dumbbell of this. We have got this commercial business that is based on lower-priced medicines and difficult-to-treat patient populations, coupled with this new emerging opportunity in a much more specialty, higher-priced, rarefied era of a rare disease. Excellent. Let's start with the base business and just talk through the three key products and just the growth dynamics for this year. I don't know, Blair, maybe you want to talk about VIVITROL a little bit. Where's the growth coming from? Where's the marketing kind of evolving? Yeah, no, I'm happy to do that. I think, as Rich said, this is a business that we've been building for a number of years across these three products. We generate over $1 billion a year on these assets. It's a highly profitable business. I think it's something that people often overlook. I mean, we guided to something like $310 million-$340 million of adjusted EBITDA this year. That's back on the back of growth of these products. I think if you look at VIVITROL, which is our largest product in the portfolio, it really is a unique product in that it's two indications. It's highly dynamic. We have about single-digit growth rates, mid-single digits with VIVITROL over the last couple of years. What's underneath the surface is two very distinct markets. There's alcohol dependence and there's substance use disorder. If you look at the alcohol use dependence, it's become 80% of the business over the last few years. It's growing at double digits. What that means is that we focus pretty much all of our marketing and resource efforts towards that alcohol dependence indication while we continue to support the opioid dependence marketplace. We see that product continuing to grow for the foreseeable future. We have a competitive entrant coming in in 2027, which we're preparing for. We see this product having quite a long life beyond that entrance. We have our psychiatric franchise, which has been quite a growth story for the business over the last two years, really driven by LYBALVI, our oral antipsychotic for the treatment of schizophrenia and bipolar disorder. I think what makes it such a unique product is it's underpinned by olanzapine. We've really worked with this product to mitigate the metabolic side effects associated with olanzapine delivery. I think we occupy a unique space within that switch market where patients who are looking for more efficacy, who are looking for a change in their medication, LYBALVI provides such a great option for them. The last few years, we've really been building on breadth and depth within that physician population. We're getting really great feedback from both physicians and patients on LYBALVI. We see that as growing well into the next number of years. Our other product in the space is Aristada, a long-acting injectable. It is a really great product with lots of options for physicians and patients. The market's a little more mature, so it's got a slightly smaller growth rate. Again, together, when you bring these all together, it's a robust portfolio for us, which drives that profitability and allows us to fund the pipeline moving forward. I know there are a lot of questions about a new schizophrenia entrant over the past couple of months from Bristol, how that would impact LYBALVI. What are you hearing? What do you think so far? I think first and foremost, I think a new entrant in the space is fantastic for the field. A new mechanism is something people have been looking at for a long time. I think it's going to take a little while for physicians to understand how to best use this medication in the marketplace. We are seeing a lot of people wanting to try this and use it in their patients. It's a little unique in that it's a couple, it's two doses a day. There are some complications with it. I think that any new tool in the box for these physicians is a good thing. Now, Bristol's really hit this with a hammer and come out there really strongly with trying to get access to physicians and to drive awareness. We've actually expanded our sales force on our psych franchise by about 25%-30%, just to mitigate that impact on LYBALVI and continue to remind physicians of where LYBALVI can best play in this marketplace. Yeah. Mark, let me just add on that. What many investors don't realize is that the average length of therapy of a patient with schizophrenia on medicine is six months. Unfortunately, when Blair says it's a churn, it's a switch market, the patients, nobody displaces somebody off of medicine that they're doing well on. The patients tend to just relapse and cycle. We like the idea that there's more dialogue in the schizophrenia market about efficacy. If people are talking about efficacy and mechanism, they want to talk about LYBALVI because we have such a highly established clinical base of evidence over many years. Hopefully, we have to maintain our share of voice. I think if people are looking for better outcomes in schizophrenia, that's good for patients. That's probably good for LYBALVI. Yeah. Good. Okay. Let's switch to the pipeline of orexins. Let's start with something that I think is still a little confusing to people. That is, how many patients are there really out there? Are they NT1, are they NT2, are they IH? I thought at your analyst meeting last summer, you were probably the first company that kind of really explained this and the evolution of the number. I think it's important. I think you might want to spend a minute or two just to talk about the numbers out there. Sure. I mean, it's a surprisingly large market for an orphan indication. I think as you look at this patient population, one of the things that characterizes it, regardless of what indication you have, is poor diagnosis. These patients go through a bit of cycling as they're progressing through their disease, where physicians don't really recognize exactly what's happening. If you get, though, to the core numbers, I think narcolepsy is encompassed by two separate indications. Narcolepsy type 1, which is a deficiency of orexin, it's characterized by excessive daytime sleepiness and cataplexy. You have narcolepsy type 2, which is maybe more of a normal orexin tone, maybe some dysfunction in signaling, but also leads to excessive daytime sleepiness, but with the absence of cataplexy. These two groups comprise about 200,000 patients on the prevalence perspective. Half of those patients are diagnosed, and 80,000 of those patients are treated with drugs. When you look at the overall treatment paradigm with these patients, 16,000 of them are on oxybates. The rest are treated with things like stimulants and antidepressants to deal with their symptoms. You can add to that idiopathic hypersomnia, which is really a diagnosis by exclusion. Everything that does not fit into those two categories kind of flows into that category. There are about 40,000 treated patients in idiopathic hypersomnia. Right now, you can kind of aggregate our markets to about 120,000 currently treated patients in the marketplace. The NT1 versus the NT2 also. Those interesting numbers. Yeah. I think that people are still trying to understand the relative difference between these two populations. I think the prevailing wisdom a long time ago, based on some very small studies, was that there is about twice as many NT1 to NT2 patients. I think what we've found recently, if you look at the current treatment paradigm and claims databases, is that it's actually the opposite. There's about twice as many NT2 patients as NT1 patients. For us, we're sort of indifferent to that because our medicine is being developed across all three indications. We have doses to treat that. We're sort of indifferent. It is important to understand where these patients come from. Right. So Rich, let's talk about the data that you have so far and talk about the data that you've also seen from anyone else out there. What do we feel good about so far with orexins? I think categorically, I think you'd have to be impressed with our data and other people's data that overall, you can see that these agents are driving significant wakefulness in patients. Overall, in the aggregate, you're seeing mild to moderate, well-tolerated profile for the drug. Hopefully, that continues to bear out. That's our assumption. Our design intention from the outset is being manifested in the clinic. That's what we're excited about, in that this is more than about selectivity and potency. If you think about it from a commercial perspective, we thought a couple of things were critical: once-a-day dosing and a range of doses across all three diagnoses. Why? Not just for increasing the size of total addressable market, but the differential diagnosis in the real world is actually quite complicated. NT1 to NT2, you'd think that's an easy differential diagnosis. It's not because sometimes cataplexy can be quite subtle. Differential diagnosis between NT2 and IH, very difficult. It really depends on access to some fairly sophisticated sleep lab stuff to make the differential diagnosis. That often doesn't happen in the reimbursement environment that we have in the United States. From the outset, we'd like to develop a drug. It's once-a-day dosing with a therapeutic index that's wide enough to dose it across the range of doses that's expected to be used across those three diagnoses, with the a priori assumption that NT1 would require a lower dose, NT2 and IH would require somewhat of a higher dose. All that's bearing out of the clinic. What we've shown with our data in our 1B program, which has been the launchpad for the broader phase II program, was dose-dependent increases in wakefulness, far exceeding what people would have seen with oxybates or other things in the NT1 population at a series of doses, an NT2 population at a slightly higher series of doses, and in IH as well. It is almost boringly predictable the way the drug is behaving. With those data sets, with the caveat that those data are in single-dose crossover studies in 1B, we do not have the fully elaborated safety data over multiple weeks. That is what we are doing in phase II. At that milestone, that hit all of the design criteria that we were hoping for. Now in phase II, what we're doing is we're exploring a range of doses, three doses in each study across a well-powered study, an N of 80 over multiple weeks, double-blind, followed by a seven-week open-label extension. That gives you that. I think the only relevant comparator to those data are what you've seen from Takeda, who have been the leader in this field from the outset. I think that the difference between our data and their data is that they've completed their phase II program, but they're testing a twice-a-day drug with one principal dose that they've identified at the end of their phase II program, given twice a day. We expect to be behind them with a superior offering across all three indications for the once-a-day dose. Why are they doing twice a day? Because of the pharmacokinetics of their drug. I think they've shown some data on this where by giving it, it's not a classic BID dose. It's not morning and evening. It's morning, followed three or four hours later by another dose, which sort of bumps the PK, but doesn't keep it out so late that it keeps people up into the evening. It is sort of logical based on the PK that they would have with that. Your product gets you the same type of curve without twice. Correct. It's actually, we think it's probably a better curve because it's trying to more mimic the natural diurnal cycle of orexin. Think about what happens when you wake up in the morning. Your orexin levels begin to rise. They sustain wakefulness during the day, and then they get tapered off at night so you can go to sleep. That actually is an important part, Mark, because what we're measuring in the narcolepsy studies is the time that people stay awake in a dark room, basically. That's a fairly blunt instrument. What it isn't capturing, which we think is going to be an important feature of these medicines in fullness of time, is the quality of that wakefulness. If I kept you up for many hours of the day where you were agitated, that's not high-quality wakefulness. I think the promise of the orexins, because orexin is considered to be the "master regulator" of wakefulness, what does wakefulness mean? Wakefulness means as you get up in the morning, your attention focuses, your vigilance increases, your mood elevates, your heart rate increases, your blood pressure, that autonomic nervous system fires up. The probability in our view that these drugs only affect the number of minutes you stay awake in a dark room is very low. I'm sure you'll get to this, but that's why we think there's logical adjacencies once you establish the beachhead in narcolepsy as to why these drugs should be used in other indications. Talk about this potency-selectivity discussion a little bit and where you come out on it. Potency and selectivity are the sine qua non for participation in this space, meaning there's an orexin 1, there's an orexin 2, there's different you have to make molecules that are very specific, Orexin 2 receptor agonists. That's difficult to do because these are GPCRs, G-protein coupled receptors, in the brain across behind the blood-brain barrier. You are making a small molecule agonist of a GPCR, but that's the beginning. It has to be very potent because we've seen from the first-generation compounds, the first-generation compounds had blood pressure and heart rate effects. You need more potency to separate from those effects. You need selectivity from the orexin 1 system as well. You have to make it orally bioavailable. It has to cross the blood-brain barrier. It has to get to the target tissue in the brain. It has to stay there in a waveform that's consistent with the sleep-wake cycle. It's really, really challenging. Potency, if I told you I had a drug that had a certain potency, my view is that the potency in vitro only matters when you see it in patients. How many milligrams do you have to put into somebody's mouth to drive wakefulness in a patient with NT1 or NT2? That's the potency that matters. Because if you have something that's super potent in vitro, but has very bad oral bioavailability, it doesn't cross the blood-brain barrier. That potency doesn't matter. I think you've heard a lot of sort of shenanigans around trying to compare drugs based on in vitro potency. I would just say you can't get into this game unless you have highly potent selective molecules. We'll see how they selective. The selectivity issue that's key. Critical. On this one. Yeah. Because of the off-target potential. Correct. Yeah. Takeda's kind of set a bar for NT1, I suppose, right? They're the first one out with a much larger phase II study. Do you look at that and say, well, if we can match their efficacy and we've got a clean safety profile where once a day, that's great. That's a great outcome for us, or? I think that's sort of our baseline assumption, not to sound grandiose here, but I think with one dose, Takeda has demonstrated that orexin 2 receptor agonism far exceeds what you saw with other existing medications. Safe, well-tolerated, patients like being on it. What we think is going to be useful, given the variability in the disease, also in the variability in what patients want out of a medicine, is to have a range of doses. You might want to go to bed at 8:00 P.M. every night. I might want to go to bed at midnight every night. We might have different expectations about what we want. Not withstanding, as we move into NT2 and IH, just the variability of the disease. NT1 patients are probably more consistent in their clinical presentation in terms of their sleepiness. You have even seen from our data, NT2 and IH patients, some of them stay awake quite a long time in the MWT test. A range of doses given once a day, I think, is going to be a major competitive advantage. We expect to recapitulate efficacy à la Takeda and maybe even drive more at higher doses. Does that come at a cost of more AEs? We will see in the data. That is what CNS drug development is about, creating this range of effective doses that physicians and patients can choose from. You think this choice of cross doses is going to be important for narcolepsy and obviously also additional indications down the line for you, right? I mean, which I want to get to. You are saying specifically in narcolepsy, you think that different people are going to want to take a smaller dose just because they know that is enough for them to get them through whatever they need. That may be one component. The other component is that there's going to be different clinical presentations of patients with NT2. For example, we have people in our NT2 study who have sleep latencies of they're awake for 25 minutes in the MWT. We have other ones with NT2 who look like NT1 patients. We might need a different dose for those two patients. If you only have one, you only have one. The other thing that's turned out to be serendipitous is that the NT2 doses are sitting right adjacent to the NT1 doses. In our phase II, we're testing 4, 6, and 8 mg. In NT2, we're testing 10, 14, and 18. Think about the flexibility that gives you with the differential diagnosis because you might have a patient with notionally NT2, but their presentation clinically is more like an NT1 patient. They can use an NT1 dose and vice versa. Talk about side effects for a second. Let's go through what are on target, what are off target, what are things that you think we really need to be watching? I think the data so far are showing that the principal on-target effects that you're seeing in a dose-dependent fashion in most studies are insomnia and what's called polyuria, urgency to urinate. The insomnia comes in two flavors, you could think about it. One is a measure of efficacy. If I give you an orexin agonist at a certain dose, we can keep you up all night. The AE is a different one. That's where often when you switch people to new medications with narcolepsy, their rhythms change and they just have trouble going to sleep. What Takeda's data showed from their orexin study over eight weeks was that that insomnia largely disappeared after the first week. Patients got used to it. You got used to it. At the right dose, we don't expect any of that efficacy level to drive insomnia. The polyuria is more interesting because it's definitely on target and it appears to be dose-dependent. It also appears to resolve over time because we're not looking at increased urinary output. It's just certain people feel this urgency to urinate that they didn't feel before. Takeda has suggested also in their eight-week study that that diminished after the first week as well. We expect to see the same for both. There's been a lot of talk from investors about what we've classified as visual disturbances. We saw one in our NT2 patient population. We saw one in our IH population at the 25 mg dose that we're not testing in phase II. People ask us, is that on target, is it off target? We don't know yet. With N of one, you don't know. There's a plausible hypothesis why it could be on target, dealing with this whole idea of activating the autonomic nervous system, pupil dilatation or constriction. What we've seen so far in those two cases were both mild, meaning they were noted by the patient, but they didn't affect them. One was noticed that the light was brighter when they turned on the light after the Maintenance of Wakefulness Test. The other one reported blurry vision, mild for an hour or so. We'll see. That's why you run phase II. We'll see whether if it's mild and transient in a small number of patients, it won't matter. It was one in the NT2 patient. One in the IH. One in the IH patient at what dose? 25. What was the most important thing of that? I mean, are you even going to 25 dose? No. 18 is the high. 18 is the high right now. If it's an on-target phenomenon, we'll see it. You'll see it at 18. In a larger population. The goal of choosing 18, by the way, was not to what people have to remember. When you're developing drugs, you want to know what happens at the end of the dose spectrum because in the real world, you'll have super slow metabolizers, for example, or someone will take three pills when they should have taken one. You want that in your label. FDA wants to understand, and we want to understand. Takeda was unable to explore those edges of the dose response curve because of the limitations of their particular drug. That's fine. We will. That's going to contribute to the whole field. Yeah. What about tachyphylaxis here? Are we seeing anything there? Are we concerned about it? No, we wouldn't see it in our studies given the way they've been designed. We will see it in the phase II if it's there. Takeda did not see it. They saw no diminution of efficacy between week one and week eight in their eight-week study. Yeah. Yeah. The two studies that you've got going on right now, just give us a sense of how enrollment's going. Obviously, there's a lot of people enrolling studies right now, so it's kind of a reasonable question. Yeah, it's going well. I mean, I think by the time of our Q1 call, we should be able to give you guys really high precision about when we're going to be done. We're on track for being done in the second half in both of them. They jockey for position which one's going faster or slower depending on week by week. Coming out of the holidays, where enrollment drops in January, February, March, we're enrolling a lot. In fact, we're activating enough sites in phase II where a number of the sites won't be able to contribute very many patients. That's because we're preparing for phase III. The secret here is to pass the baton from phase II to phase III because phase III, unlike a psychiatric study, we know exactly what the phase III looks like right now. It's a clone of the phase II. MWT, Epworth, certain duration, randomized, it just turns the card. You decide the dose. Yeah. The efficacy, you're not powering these things for efficacy because the efficacy manifests so early in the we had a P-value with four patients in our NT1 study, right? That's how profound the efficacy difference can be at the right dose. We could basically describe the architecture of the phase III program to you right now with the caveat. When we finish the phase II, we're going to go to FDA and say, okay, what's the most expedited path to approval? We're one of the only players in NT2 right now. Do we have a chance for breakthrough designation in NT2, for example? Does that open up a more expedited pathway? All this is yet to be determined. It will be based on the quality of the phase II data. Paint the picture for these drugs in non-narcolepsy patients. What do you see as the opportunity? The way to think about it conceptually is in the concentric circles, NT1 is at the center. It's essentially nature's knockout model. If you knock out orexin, what's the phenotype? You have excessive daytime sleepiness. You're basically asleep all the time. You know that if you replace orexin there, you're going to have a therapeutic effect. That's been demonstrated by us and others. The next shell is NT2. As Blair said, maybe aberrant in orexin signaling, but if you do a lumbar puncture, you'll find orexin in the system. We've shown in those patients in a dose-dependent fashion, we can drive wakefulness for them as well. The next shell is idiopathic hypersomnia. It may have nothing to do with orexin. Just people tired all the time. Guess what? We showed dose-dependent increases in wakefulness in those patients as well. That adjacency is a critical one because that next shell behind that is patients that might not even be diagnosed with an excessive daytime sleepiness diagnosis. It could be a mood disorder characterized by anhedonia, and tiredness all day. It could be a neurodegenerative process where the clinical presentation is a lot of excessive daytime sleepiness. It could be an ADHD indication where attention and vigilance is relevant. You saw in our investor day, which is still on the web from October, preclinical work that we've done in various translatable model systems in animals that suggest very clearly where these drugs could be used outside of narcolepsy. It is just a responsible way to proceed stepwise from the most logical center of the bullseye out. We have put two new additional molecules into development that'll go into the clinic this year to begin to probe these other indications. We're not waiting. Operationally in the company, we're already preparing for a narcolepsy drug. We think we have one with all the appropriate caveats and the risks, and we all know that. Operationally, you got to prepare for these things. We're already thinking what's coming beyond that. Are we going to learn this year what those other indications are? No. I think we're going to keep it pretty close to the chest until we finish the SAD-MAD, single ascending and multiple ascending doses for the single agents. Then we'll go into the translatable study. It's really next year as you'll need to tell us probably what it is. I mean, it's safe to say that drugs that help you feel more awake help Alzheimer's patients, Parkinson's patients, all of these patients, like you said, depressed patients. These drugs sometimes are sedating, right? That's just a natural side effect. You could just take this drug in addition, right? There's so many interesting clinical applications to market. Exactly. That's why we're not going to tell competition about where we're going because. I say thematically. You know we've been through the wars of developing drugs for major depressive disorder and these highly heterogeneous clinical diagnoses based on DSM, where you get a whole mixture of patients and you hope for signal against a backdrop of a lot of noise, high placebo response. We don't want to do any of that. We want to go into targeted patient populations where the clinical presentation maps onto the deficiency or maps onto the circuitry that the orexin system is driving. That has to do with mood and attention and vigilance and things like that. In the last 30 seconds, maybe anything that we haven't hit, anything that you feel like is just misunderstood and you want to hammer out to kind of hear? Thankfully, I think we're moving past the phase. We spent a lot of time last year trying to reorient because Alkermes has been quite an evolution. You know better than anybody. You've watched it all happen. This thing is now a profitable pure-play neuroscience company with a pipeline. That wasn't the story five years ago. It's taken a lot of time to educate. Boy, it feels good right now. We have risks ahead of us in this business, but we couldn't be more pleased with the setup going into the second half of the year. Yeah. Good. Okay. All right. Let us know when the data's coming. We'll be at the sleep meetings. Thank you for joining us. I just want to have it before everybody else, but that won't happen. Thank you. Thanks for joining us, guys. Appreciate it. Good to see you.