Okay, let's get started. Good afternoon, everyone. Day two of the 36th Annual Piper Sandler Healthcare Conference. This is David Amsellem from the Biopharma team here at Piper Sandler, and we're delighted to be joined by Richard Pops, CEO of Alkermes, and thanks so much for doing this. You know, now you're here in the frozen tundra as opposed to sunny Florida, but, you know, we'll try to make it worth your while, so I'll just start right in with questions. There's obviously lots to talk about, so you had some recent comments on your third quarter call about spend in 2025 and EBITDA, so I guess just big picture, walk us through how to think about cost structure going forward, particularly in the context of the advancement of 2680 and other orexin agonist candidates, and also the commercial support of Lybalvi, obviously a lot going on. So help us better understand how to think about 2025 in terms of the cost structure and spend. First of all, good to see you. Nice to see you too. Thanks for hanging in at the end of the day of a long day. So before getting, I think the cost structure is one of the least interesting parts of the company at this moment in time. I started with it. I think the most important part is just the transformation of the business over the last couple of years, which I think is being recognized broadly for the first time now. And that is how we've built the company now in this configuration where we have a very profitable, pure-play neuroscience company with what is emerging to be a really exciting pipeline of products that start with 2680 in narcolepsy. I don't think it ends there. And so what we've been trying to do from a financial point of view is streamline the cost structure, get the company into an operating position to allow us to drive profitability for the long term while funding in a non-dilutive way, if you will, the expansion of what we think is going to be a really exciting pipeline. So what we did a few weeks ago around the earnings call was just try to get everybody on the same page on the sell side, particularly for 2025. There's a wide dispersion of, I think people just hadn't updated their models. And so if you took the various elements of the business that changed during 2024, selling our ethylene facility, ending the royalty arrangement with J&J for Invega Sustenna, changing manufacturing relationships, if you just flowed all that through and rebuilt your model, you would have been real close to what we guided to. But now we just help people see it for what it will be. So hopefully when we give our formal guidance then in February, it should be within a bandwidth that most people are already well comfortably there. So looking at R&D and the pipeline more holistically, so I'm thinking about business development, M&A, and licensing. I mean, obviously, you're full speed ahead with the orexin programs. But I guess the question here is how big of a priority is the addition of another asset or assets to bolster the neuropsychiatry pipeline? I think it happens as a matter of course. If we're going to be a freestanding, independent neuropsychopharmacology company or a CNS-focused company, the pipeline is going to expand, and it expands along organic lines, i.e., what we're doing with orexin, but also expands in non-organic ways or orthogonal ways that leverage your scientific capability and your commercial capability and help you build out a multidimensional business. So in terms of what you're prioritizing, well, there's a couple of questions in here. It sounds like you're prioritizing bolstering the pipeline at various stages of development, and it sounds like you're leaning towards that as opposed to a commercial stage asset where you can leverage your commercial infrastructure. I mean, is that a fair way to think about it? I think we would be very happy doing deals in both of those domains. It would be really wonderful to leverage the commercial infrastructure. It's big, it's credentialed, it's expensive, and now it's profitable after getting multiple products into it. It's also scalable. The only limitation is that there's just not that many products in that space to put into it. But we're assiduously looking for those opportunities at all times. And also, as products emerge through development in the hands of small companies who are faced with the daunting prospect of building that commercial capability for a single product, it's probably bordering on uneconomic to do so if you're talking in certain therapeutic categories. Yep. Whereas if you did it with us, it could be profitable for both of us. In terms of access and capital, levering up, doing something on a grander scale, I mean, is that something that you're contemplating? Not at the moment. We see the potential for really significant valuation expansion based on the maturation of the orexin portfolio. So we're going to ride that curve for a bit. With that said, we have $1 billion of cash. We have the ability to lever if we needed to. We don't see any gun to our head because we see the business evolving along these lines that we articulated a couple of years ago. It seems to be evolving the way that we planned it. And so far, I think it's working. Let's talk about all things orexin. We'll get to the base business, but obviously much to talk about regarding 2680 and the other orexin and products. You had an orexin event recently. You announced that you were going to initiate a phase II in idiopathic hypersomnia for 2680. But you had previously talked about IH with a different orexin. Just help us understand your thought process here. Was it based on commercial considerations, clinical considerations, combination of both? It was an interesting journey because when we started off in the development program of ALKS 2680, which is our oral orexin 2 receptor agonist for narcolepsy, we thought at the outset we would develop for NT1 and NT2, and in so doing, that's a single orphan indication, narcolepsy, because the drug would potentially not be subject to negotiation under the IRA in nine years' time. When we completed the phase 1b study and saw the data from the NT2 and the IH cohorts, we went and visited with patient groups and also with clinicians, and it became abundantly clear to us two things. One is that IH patients are really anxious for new medications, and number two, that the differential diagnosis between NT2 and IH is so fluid that it's almost an arbitrary distinction. It almost would have been unfair to develop it in one lane, coupled with the fact that there are 40,000 patients within IH at least, and it's a major economic opportunity for nine years. Finally, we have to believe that the IRA looks the same nine years from now as it does today. I think the probability of that is approaching zero. All those things led together to say, you know what, 2680 looks like a fine drug for IH. We have a head start. Let's go. Okay, makes sense. So now you have phase II studies in NT1, NT2, IH. So with that in mind, some more review questions, but talk about the dosing ranges across these studies. And what I'm getting at here is dosing flexibility. This is something I've heard a lot about from key opinion leaders, the need for dosing flexibility. So in thinking about wakefulness promotion, how important is dosing flexibility within this new orexin category? I think it's critical. In In our development of a target product profile, ideally, we would have a drug that could be used in NT1, NT2, and IH across a range of doses so that it satisfies a couple of criteria. One is that the disease itself, if you take all three of those populations, is quite variable. So it stands to reason that different doses may be more or less effective depending on different clinical presentations. Number two is that patient preferences differ as well. One person's idea of how long they want to be vigilant and awake during a day may be different than somebody else's. Another argument for dosing flexibility. So in our conception of the product, the idea was tested in NT1, NT2, IH, find maybe what is the modal dose, the anchor dose in each of those indications, and provide dosing flexibility around that to accommodate the variability that we just discussed. Yep, makes sense. Another thing that comes up, a couple of other things that comes up in talking to key opinion leaders on the orexin axis, and is, one, the extent to which by improving daytime wakefulness, you can ameliorate, you're also ameliorating sleep fragmentation. Another area of interest is the extent to which the category can ameliorate sleep inertia. And this is a heterogeneity. There's a lot of heterogeneity here in these populations. But wondering if you could talk to those items in terms of the early body of data for 2680. If we were to say with 2680 what we're going to do for sleep architecture, that'll require repeat dosing in phase II. We will begin to develop those data sets in this ongoing phase II study where patients will go in for polysomnography in the sleep lab during the course of the six-week double-blind period. But with that said, the theory from the folks who really believe in the orexin hypothesis is that in NT1, for example, NT1 is a deficiency of these orexin neurons. And so nature has provided the knockout model. If you knock out these neurons in the neurotransmitter, what's the phenotype? The phenotype is excessive daytime sleeping and cataplexy. If you replace the neurotransmitter with an oral small molecule equivalent of it, and you do so in a diurnal pattern that mimics the natural sleep-wake cycle, you've essentially addressed the cause of the disease. So there's a hypothesis that in so doing, you should reestablish normal sleep architecture in the evening as well. That's a theory. And it may be too idealized a notion for even to be practical. But I think that there's a reasonable case for doing the experiment and seeing what we learn. Yeah. And what about sleep inertia? I mean, this is something that you see is particularly troublesome in IH. And this might be more straightforward in terms of addressing here, but is the idea of a once-daily morning dose? I mean, is that something where, I mean, you have to see what insomnia looks like, et cetera, et cetera. But is it your view that ultimately by ameliorating EDS, you're going to ameliorate sleep inertia? I think the hypothesis though should correlate. Yeah. Okay. So So before we go into some commercial considerations around the orexin, wanted to come back and drill down on safety and tolerability. And this obviously comes up a lot. One of another company talks about absence of visual disturbances and absence of urinary urgency. But I guess how would you sort of characterize what you've seen thus far? I mean, a lot of KOLs that we've talked to have, for lack of a better term, said, well, you know, these are more or less nuisance effects. In terms of what you've seen thus far, where do you kind of land on both visual disturbances and urinary urgency? It was characterized yesterday to us in a way that I thought was thoughtful, which is of the three companies who have or four companies who actually posted some clinical data, there's only two that have posted clinical data in patient population that matters, but even if you take the whole group, I think the general conclusion you can draw is that these orexin 2 receptor agonists seem to be driving meaningful wakefulness, and as a category, have been remarkably well tolerated. The side effect profile that's been described has generally been mild or moderate, transient, and as you said, these are urinary urgency, insomnia, things like that, so I think that we don't know the full profile of the safety profile of any of these medicines until they've been tested in the patient population of interest at the appropriate dose over a multi-week period. That's what we're doing right now to augment our single exposures in phase I B. But our feeling is that if the profile is borne out, what we're seeing would be on-target effects highlighted probably by polyuria, the urinary urgency. And another company's data showed that it was actually diminished over time as patients accommodated that feeling, as did the insomnia. So the visual disturbances, quote unquote, that we saw, we saw one in the NT2 cohort and one in the IH cohort that doses were not testing in phase II. And that's not to minimize it. It could be an on-target effect. But if it were, what we saw in the one was a photophobia, a mild case of noticing the lights look brighter. Mild meaning was noted by the patient, but didn't affect them. Another blurred vision in another patient in another cohort, again, mild and transient. If that ends up being an on-target dose-dependent feature of the drug, I don't think that'll impede it at all. Yep. Okay. And I guess looking at, say, urinary urgency, I mean, to the extent that even if it doesn't attenuate or if it's not transient and it takes, say, weeks to attenuate, I would imagine that's something that could be managed pharmacologically relatively reasonably. In the data set that was presented at Houston in June from the large phase II of 861, the patient reported outcomes were outstanding. So to the extent that it was noted, it wasn't affecting either withdrawal from the study, discontinuation, or even quality of life. So I think that's probably right. The other just admonishment I would say is that no one can make a comment about the safety of their drug until you've tested it in these longer studies, ourselves included, right? So I just take it with a grain of salt if anybody says their drug has no side effects and is super effective until you test it in patients over time in the dose range that's appropriate. I think there's also context. I mean, Oxybate has been a standard of care for almost 20 years and has quite a bit of baggage. And yet there's tens of thousands of patients who have been on it and almost 20,000 patients who are on it and were willing to tolerate. Read the label for stimulants. Right, exactly. So what people often, and I was unaware of until we actually did the patient research, is just how degraded the quality of life is for patients with NT1, NT2. It's really tough to see even with the medicines that exist. And so there's a real tolerance for more and more efficacy. And I think that's what the promise of the orexin 2 receptor agonists. So here's a commercial question. I think you've opined on this in the past. I think it's kind of interesting is just on the pricing of the orexin 2 receptor agonists. And any views on how you think Takeda is going to approach pricing, just bearing in mind that they're coming in only in NT1? And I guess what kind of implications would that have for 2680, bearing in mind that you'd be coming to market potentially in NT1, NT2, and IH? I obviously can't comment on what another company's strategy would be with respect to pricing. But I think what are the relevant data points? Oxybate's being priced around $200,000 a year and getting reimbursement at those levels. 80,000 patients diagnosed and treated with narcolepsy in the U.S. Only about 16,000 of them getting Oxybates for the various limitations we talked about before. And about half of the doctors, sleep specialists in the REMS program for Oxybates. And the other interesting data point is that the average price of an orphan medication in the U.S. these days is about $350,000 a year. So to command values, my own personal view, to command values of that order, $200,000, $300,000, you have to deliver really transformational medicines to patients. And I think that will be borne out by the data. If we can do that, if we can really transform the treatment of narcolepsy and IH, then I think these will be premium price products. Yep. Okay. So we've seen over the years other companies looking to develop wakefulness-promoting agents and indications outside of narcolepsy and IH. For instance, Harmony looks at Pitolisant and say EDS associated with Prader-Willi syndrome, among others. So with that in mind, how do you think about 2680 or other orexin agonists in the pipeline in sleep-wake, regarding sleep-wake conditions outside of narcolepsy and IH? Is that something you have interest in exploring? No, we're super interested. I think the potential or the probability of having a really important narcolepsy drug that doesn't read on to other indications is very low, and it goes back to the neurocircuitry, which, in medical scientific history, is relatively new. This bundle of neurons and their function were only discovered 20 years or so, and, not just if you understand the architecture, the circuitry of what the orexin system is driving in the brain, it's not just a master controller of wakefulness. It's things associated with wakefulness, probably cognition, vigilance, mood, things like that. So just looking at the projections of these neurons to other regions of the brain and looking, and we've shown some of these data using microdialysis and other effects on other neurotransmitters, I think that the probability of these drugs being used in other settings is very high. Now, the further refinement of that thought is even if you just draw wakefulness in certain indications, it may not even be disease modifying, but it could be really helpful for two patients if their disease is characterized by this excessive onerous daytime sleepiness. Add to that then if you actually are affecting circuitry directly relevant to the condition itself, I think there's a real exciting potential there. Yeah, well, I think just looking at sleep-wake, I mean, what we've seen over the years, and again, we'll get to things like mood and cognition and attention, et cetera. But in sleep-wake, we've seen companies, I mean, I could go back to when Cephalon had exclusivity for modafinil, and they were looking at it and yeah. Shift work. Shift work. Jet lag. Jet lag, exactly. That's right. EDS associated with depression. And there were many other studies. And I think there are limitations to doing that. But I guess the question here is, say, with 2680, you have your sort of beachhead with narcolepsy and IH. Do you look at other sort of rare neurologic conditions where EDS is a hallmark symptom? Does that make sense? We do, for sure. And then also with new chemical matter, we look at some of the broader market opportunities with lower price products with maybe different pharmacology or combination pharmacology. But just back to that point about sleep-wake, what's fascinating to me is you think about how much energy was dedicated towards sleep compounds. And then you ask yourself, why? Why do we develop sleep medicines? So we have better wakefulness during the day. So what's exciting about the orexins is that for the first time, we're interrogating the wakefulness side of the brain rather than the sleep side of the brain. So we're directly going after what we're seeking to affect rather than indirectly by improving sleep. And I think that's a really new frontier. So regarding the other orexin agonists that you're moving into the clinic, just give us a brief refresher on their advancement into human studies and what we should expect over the next year. And you highlighted a lot of preclinical data, very interesting preclinical data. I guess any new thoughts on what you're thinking regarding the kind of indications you're looking to explore with these additional agents? The necessary prerequisite for advancing orexin 2 receptor agonists into human studies is a fairly elaborate constellation of attributes that begin with potency and selectivity, but include oral bioavailability, blood-brain barrier penetration, and PK. All of these things together are a pretty significant filtration of a lot of chemical matter. We happen to have a library now of compounds that are meeting those criteria. The first step clinically is just to advance them through the classic single ascending dose, multiple ascending dose, characterize them and their pharmacology in patients. From there, then we're going to move into what we think will be highly translatable first experiments in patients with disease where there are biomarkers or imaging or other ways of ascertaining target engagement early on. Because we're looking under the lit lamppost. We know what the circuitry does in terms of its effect on mood and its effect on vigilance and attention and things like that. But also, to your earlier point about other orphan indications where you have chronic excessive daytime sleepiness, as a matter of fact, you can move right into those studies. And the interesting thing about those assays, you know very quickly whether you're having an effect on wakefulness. It's not a thing where you run three months double-blind, hope to unblind, there's large placebo effect. There's a pretty quick clinical readout. So what we're hoping to do is qualify these new medicines early from the SAD/MAD perspective, and then very quickly get them into settings where we all can determine whether we're creating new value. Yeah, and what you mean creating new value, at least quickly determine their wakefulness properties, and then from there, look at other. Their wakefulness properties, or even in highly translatable human systems, attention or mood as well. Okay. So just to be, as a, I guess, a reminder here, so two assets, two shots on goal going into human studies next year. Yeah, we've nominated two. One is almost done with GLP tox, the second one is going into GLP tox now. So I'm not sure whether we'll be in the clinic with the second one next year. Yes, we are. Okay. Yes. Just real quick, got to ask a question off the bat. Just as we move into 2025, just regarding the contracting landscape and with commercial plans, and also particularly just with Cobenfy in the market, just how should we think about the trajectory of the product given more commercial contracting, given the entry of a new product that a lot of people are excited about? Just overall, what you're thinking about the trajectory of the product next year. We'll continue to grow, evolve. And this category is quite promotionally sensitive. So the principal operational change with the launch of competitors is just maintaining share of voice. So you heard us say we're going to expand our sales force into 2025 to maintain that share of voice. Lybalvi has a very strong positioning in the schizophrenia market, bipolar market, because of its efficacy. And that's credentialed because of the long clinical history of olanzapine, plus multi-year data on Lybalvi itself. So as you know, these are markets where we're not displacing patients off of medicines in favor of their medicines. It's a switch market. And so we'll continue to be right in the mix for that branded switch market. And if we maintain share of voice and continue doing what we do on the personal and nonpersonal promotion, we'll continue to grow the product. The headwinds we all have to be careful of in this industry are gross net expansion because of payer control, and so we've been fastidious on the contracting, and it's worked really well for us so far. I'll leave it there. Thanks, Richard. Thanks, everyone in the audience. Thank you, David. All right.