All right. Good morning, everyone. I'm Sandy Coombs. I lead Investor Relations here at Alkermes. I'm happy to welcome you all today here in the room and on the webcast. I know it's a busy time of year, so thank you for making the time to learn a little bit more about Alkermes' orexin portfolio. Some housekeeping items for today. There will be two opportunities for Q&A during our roundtable panel with Dr. Maski from Boston Children's and Dr. Plante from the University of Wisconsin-Madison. Monica Gow, co-founder of Wake Up Narcolepsy, is here to join us, and we're fortunate to have them here with us, so please take advantage of the opportunity. During today's presentation, we will be making forward-looking statements, so please take a look at our SEC filings for important risk factors that could cause our actual results to differ materially from those expressed or implied in our forward-looking statements. We undertake no obligation to update or revise the forward-looking statements provided on this webcast as a result of new information or future results or developments. With that squared away, it's my pleasure to introduce Dr. Craig Hopkinson to provide some introductory remarks and the agenda for the day. Thank you. Well, good morning. I'm Craig Hopkinson, Chief Medical Officer and Head of R&D at Alkermes, and on behalf of our scientific and clinical development teams here, I'd like to thank you all for joining us here this morning. We've been looking forward to a meeting of this type for some time now, as it gives us an opportunity to share some of our developing insights into the potential utility of therapeutics that harness the orexin pathway. Orexin is considered to be the master regulator of wakefulness. As you know, the first embodiment of the orexin-2 receptor agonist pharmacology has been focused on the restoration of orexin signaling in disorders where excessive daytime sleepiness is the key symptomatic domain: narcolepsy Type 1, narcolepsy Type 2, and idiopathic hypersomnia, or NT1, NT2, and IH, as you'll hear them referred to throughout today's session. Alkermes is the only company with patient data supporting phase 2 development of an orexin-2 receptor agonist in NT1, NT2, and IH, with a range of doses expected to accommodate the spectrum of potential indications with once-daily administration. As we review the data generated across the space and the competitive profiles that have emerged, we are confident in the differentiated features and profile of ALKS-2680. ALKS-2680 results from our understanding of the critical elements necessary to design a small molecule orexin-2 receptor agonist. The program is built off of a strong scientific foundation, beginning preclinically and extending into a phase 1a study in healthy volunteers and a phase 1b study in patient populations that we intend to treat, NT1, NT2, and IH. The early clinical program was designed to provide data relating to the safety, tolerability, the pharmacokinetics, and dose response, as well as the pharmacodynamics, which enabled data-driven selection of our doses for phase 2. ALKS-2680 is advancing along a well-defined clinical and regulatory pathway. We're currently enrolling in phase 2 studies for NT1 and NT2 in multicenter global studies called Vibrance-1 and Vibrance-2. Today, we are sharing our decision to expand the phase 2 program and advance ALKS-2680 into a study in patients with idiopathic hypersomnia. This will be a phase 2 study. We made this decision based in part on clinician and patient feedback following the results of our 1b IH cohort and the limited treatment options available to IH patients. Advancing into a phase 2 study will allow us to more fully characterize the profile of ALX-2680 in this patient population. As we advance the development program, we are focused on three core elements: first, the quality of our clinical study conduct, as well as the data that we're generating. Second, the speed at which we're advancing our program. And third, integrating the principles of patient-focused drug development throughout our program. Our phase 2 program is designed to provide a strong operational foundation across all three of these priorities as we prepare to enter a potential phase 3 program. We believe that orexin therapeutics have the potential to fundamentally change the way that narcolepsy and IH are treated. All of this is exciting in its own right, but the orexin system is also associated with the activation of multiple downstream neurotransmitters and neurocircuitry. Orexin-based pharmacology has the potential to extend to multiple CNS disease settings where sleepiness, fatigue, cognition, and mood are prominent clinical features. We are leveraging this understanding and pursuing a multifaceted preclinical research program to identify the most promising lines of development and evaluating the effects of orexin-2 receptor agonists, either as monotherapy or superimposed with other mechanisms to extend the spectrum of pharmacologic activity. This hypothesis and work are the foundation of our orexin expansion strategy, Project Saturn. We're looking forward to sharing insights into this exciting work with you today. So with that as by way of introduction, this is how we're going to proceed today. Dr. Brian Raimer, one of our lead chemists and neurobiologists, will present a brief overview of orexin signaling in the brain and the role that it plays in narcolepsy, as well as its direct relevance to other CNS disease states. Understanding the biology is critical to identify the clinical opportunities. However, the complement to the biologic understanding is the ability to develop suitable chemistry, chemical matter. Medicinal chemistry has historically been an area of strength at Alkermes. Engineering new molecules with appropriate pharmaceutical properties, along with features important to the real-world needs of patients. Following Brian, Dr. Julie Himes, our Head of Clinical Development, will summarize the data that we've generated for ALX-2680 in our 1b clinical program, providing a snapshot of the safety, efficacy, and dose response across all three indications: NT1, NT2, and IH. Julie will also discuss our phase 2 program, including the study design, as well as the objectives for our two ongoing phase 2 studies in NT1 and NT2. Rapid and efficient execution of our phase 2 program is a critical priority for us as we look forward to the data readouts in our two studies next year and initiating our phase 2 study in IH. Charlie Peck, who heads up our new product planning group, will then share important insights into the epidemiology of narcolepsy and IH, along with patient research that we've conducted. This research reveals significant unmet needs of patients despite the availability of current drugs and captures the critical impacts that these diseases have on patients beyond the core representation of daytime sleepiness. These data and insights inform important elements into our clinical strategy and our clinical trial design. After Charlie, we have a thought leader panel comprised of two sleep specialists, Dr. Kiran Maski from Boston Children's, and Dr. David Plante from the University of Wisconsin-Madison. We're also fortunate to have Monica Gow, a founder of the patient advocacy group, Wake Up Narcolepsy, here with us today to share patient and caregiver insights. Sandy will moderate the discussion, which will be fueled by questions that many of you have submitted. Following our panel, Dr. Bhaskar Rege, our Head of Early Development, will outline how we use data-driven decision making in development and give you some insights into the sophisticated experimentation and biostatistical modeling that we use to rigorously explore dose response relationships to inform clinical dose selection. Bhaskar will then shift his focus to Project Saturn to outline our approach to identifying our next potential clinical candidates and indications, selecting areas which we believe have high translational fidelity. He'll introduce a framework of preclinical assessments that serve as the foundation of our decision-making process, including microdialysis, qEEG, and behavioral assays. Taken together, we use these data to identify and select potential indications and our next candidates for evaluation, either as single agents or as polypharmacy with other established CNS active compounds. Next, Dr. Julie Brooks, a seasoned neurobiologist, will share a selection of data from this program that support orexin-2 receptor agonists as a potential treatment option in a number of potential indications, such as ADHD and certain mood disorders, where we see opportunities to develop new medicines with differentiated profiles to address unmet patient needs. Now, we won't share the full extent of our work with you today for competitive reasons, but Julie's presentation will provide a window into our approach to fully harness the potential of the orexin-2 pathway. Rich will then finish up with a summary of key themes for the session and the view ahead. We are excited to get to share this data with you, so let's get started. Brian, over to you. Thank you very much for the kind introduction, Craig. I'm Brian, Brian Reimer. I'm a Ph.D. chemist by training and a research project leader here at Alkermes. I led the research team that discovered Alkermes' portfolio of orexin-2 receptor agonist, and I'm here today to tell you how the team utilized advanced molecular design principles to harness the broad potential of the orexin mechanism. Orexins, also known as hypocretins, are neuropeptides produced in the hypothalamus. Initial drug development focus for medications utilizing the orexin mechanism has been in sleep disorders, given that orexin is a key master regulator of wakefulness. But there's more to it than just wakefulness. Orexin neurons are multitasking neurons that regulate a set of vital functions, including sleep and wake states, energy homeostasis, reward systems, cognition, and mood. In today's presentation, I'll share Alkermes' approach to orexin-2 receptor agonist and how understanding complex interactions between a number of critical variables is key to designing differentiated small molecule orexin-2 receptor agonists. The broad potential of the orexin mechanism starts in the hypothalamus, colored blue in the lower center of this sagittal diagram of the brain. Orexin neurons project from the hypothalamus into multiple brain regions and modulate an array of downstream neurotransmitters. For instance, orexin neurons candidate exert central control of wakefulness, connecting with different regions of the brain associated with wakefulness, such as the dorsal raphe, basal forebrain, prefrontal cortex, and other areas in the cortex that are involved in many essential functions, including sensory processing. Pathways modulated by orexin may also be involved in the control of mood. As you can see by the dark red arrows, many of the brain regions involved in mood have very similar and may even have interacting connections with the orexin pathways. These similarities include connections from the dorsal raphe to the hypothalamus and from the substantia nigra through the amygdala to the prefrontal cortex and other areas of the brain. Pathways modulated by orexin may also be involved in the control of attention. As you can see, represented by the black arrows, some of the neural pathways related to attention emanate from the dorsal raphe to the tuberomammillary nucleus and basal forebrain. Many of these pathways, for instance, those proceeding towards the prefrontal cortex, cingulate, and cortex area, parallel the light blue pathways of the orexin originating from the hypothalamus. How do orexin neurons activate downstream pathways via the orexin-2 receptor? Initially, the orexin-2 receptor is found in its inactive state. The orexin-2 receptor is a GPCR or G protein-coupled receptor, also known as a seven-transmembrane receptor, represented here in light gray, with a lipid bilayer of the cell or neural wall on either side, also in gray. Represented on the right is a fragment of one of the orexin peptides in orange. Orexin peptides are released from orexin neurons and are endogenous activators of orexin receptors in the brain. While starting in the inactive state, orexin signaling is off. Once the orexin peptide is released from the orexin neurons, it interacts with the orexin-2 receptor. The receptor then moves to an active state, as shown by the shift from the light gray representation to the blue representation. The orange arrows highlight some of the transmembrane areas that undergo conformational and location changes that facilitate downstream cellular neural signaling via the release of G proteins. Understanding the orexin peptide interactions with the orexin-2 receptor is key to replicating this activation with a small molecule. Key activator interactions include hydrophobic interactions with phenylalanine 227, a key hydrogen bond with histidine 350, as shown by the blue circle, and by not blocking certain areas of the binding pocket, allowing movement of glutamine 134, a key step in the activation of the receptor. An orexin-2 receptor small molecule agonist that most mimics these activating interactions and allows for movement of key residues could replace the endogenous orexin peptide activation. So that being said, mimicking the interactions of an approximately 3-kilodalton or larger orexin peptide with a small molecule less than 500 daltons is easier said than done. Drug developers face numerous challenges in replicating the orexin peptide interactions with a small molecule, including balancing complex and competing critical variables essential to designing small-molecule orexin-2 receptor agonist. Among these variables, for instance, Alkermes used key orexin-2 receptor structural information to engineer in potency and selectivity into our portfolio of molecules. Together with metabolic properties, these attributes are key to enabling a wide range of doses with the potential to be well-tolerated. We also focus on oral bioavailability and brain penetration to allow for low overall dose levels, for oral administration. Particularly important for medicines seeking to mimic a natural sleep-wake cycle, we focused on molecules with suitable pharmacokinetic properties. We have a deep expertise at Alkermes in designing complex, potent, and selective molecules, integrating a diverse array of pharmaceutical properties with a particular emphasis on the relationship between pharmacokinetics and pharmacodynamics. In the case of ALKS 2680, we designed a highly potent and selective GPCR agonist. We synthesized and screened hundreds of compounds to arrive at ALKS 2680 and the other compounds in our portfolio that balance these variables. The pharmacokinetic profile is one of the key features of our orexin-2 receptor molecules, and I'd like to delve into that area in a little bit more detail. The pharmacokinetic profile of a small molecule is a key player in the balance between safety and efficacy features. Let's walk through an illustration of a few key PK parameters that informed how we approach the molecular design of our orexin-2 receptor agonist. In the diagram, the Y-axis is the plasma or brain concentration, and the X-axis represents time moving from left to right. The blue line represents an illustrative, efficacious concentration in plasma brain levels for a given indication, here using NT1 as an example. From the start of the program, we wanted to design a small molecule that would mimic the natural sleep-wake profile and duration provided by endogenous orexin with once-daily dosing. We also targeted high potency to drive meaningful efficacy with low overall doses and exposures. The black waveform line represents a hypothetical plasma concentration over time. Once the plasma concentration of the orexin-2 receptor agonist rises over the efficacious concentration level, in this example, corresponding to an indication such as NT1, wakefulness would be promoted by sufficient interactions of the small molecule with the orexin-2 receptor. While above this concentration level, the orexin-2 receptor agonist would stimulate downstream neurons and neurotransmitters, turning on the wakefulness system. Over time, as the plasma concentration decreases, the downstream signaling and wakefulness promotion would subside. This hypothetical PK profile can provide flexibility in the magnitude and duration of pharmacodynamic effect and provide differentiated molecular attributes. A PK profile can be targeted to yield dose-dependent proportional increase of AUC, or area under the curve, and a lower than proportional or non-proportional increase of the maximal concentration after the dose. The lower than proportional maximal concentration is designed to reduce the risk of tolerability issues, and I'll circle back on this shortly. As you can see in the schematic, doses A, B, and C provide different profiles and durations of effect relative to the efficacious concentration, in this case, representing NT1. Different indications may require different efficacious concentrations and dose levels. This schematic shows a second set of higher doses. In this example, that would allow for efficacious concentrations to be achieved in indications that may require a higher level of orexin-2 receptor agonism, such as NT-2 or IH. A wide therapeutic margin also allows for dosing flexibility across indications and patient variability within an acceptable tolerability range. You'll see that at the top of the graph, there is a red line representing a hypothetical tolerability limit. This concentration would be associated with unacceptable safety and tolerability profile or toxicity, so exposure levels must stay below this threshold. All these PK design principles were considered in our development of ALX-2680. We targeted high potency to allow for low doses and low overall exposures that drive wakefulness while keeping the maximum concentrations low to increase tolerability. ALX-2680 was designed to enable dosing flexibility with the potential to accommodate variability in indications, as well as individual patient profiles and treatment objectives. In this introduction, I hope you have seen how Alkermes utilized advanced molecular design principles to engineer ALX-2680 and harness the broad potential of the orexin mechanism. As you know, orexin neuropeptides are master regulators of wakefulness that work in a diurnal manner, and we designed our small molecules to mimic this profile via once daily dosing. In addition to wakefulness, orexin-2 receptor agonists may benefit additional symptomatic domains such as fatigue, mood, cognition, and attention, as we saw in the overlay of the different but overlapping neural systems. Understanding how the orexin peptides activate the receptor and cascade signaling across the brain is key to designing small molecules that harness the potential of the mechanism. Alkermes' chemistry design approach is focused on key parameters such as potency and a targeted pharmacokinetic profile that may address the needs across a range of potential orexin-relevant indications. Thanks very much for your attention, and looking forward to connecting with you after the presentations, and I'd like to introduce Julie Himes, our Head of Clinical Development. Thank you, Brian, and good morning. I am delighted to take you through our phase 1b program and tell you about our strategies in phase 2. My name is Julie Himes. I lead clinical development at Alkermes. I am an infectious diseases physician by training. I spent ten years at NIH doing both clinical as well as bench research, and then the last twenty-two years in industry. I've worked mainly in orphan diseases and rare diseases, and I have been at companies such as Millennium, Vertex, and Takeda, so let's begin with a look at the clinical features of our target indications, central disorders of hypersomnolence, including narcolepsy and idiopathic hypersomnia. As you can see, with few exceptions, the individuals impacted by these conditions share many of the same symptoms, including excessive daytime slee piness, brain fog, and disrupted nighttime sleep. While there are elements that can help differentiate these conditions, such as sleep onset, REM periods, and cataplexy, the variability and subtleties of these disorders can be challenging even for the most seasoned clinician, hence there are considerable diagnostic challenges. ALX-2680 is being developed as a potential new therapeutic option for all three of these conditions and is currently the only orexin-2 receptor agonist advancing into phase 2 in these areas. We believe that this is an important differentiating feature of ALX-2680, and today I will share the highlights of our program, our phase 1b study, and our plans for phase 2. However, there are comprehensive datasets available on our website from presentations and posters given at major medical meetings, and I encourage you to look at those. Before we dive in the data, I want to provide an overview and hit on a few salient features that further differentiate ALKS 2680. 2680 is a highly potent and highly selective molecule. And we, in addition, as Brian's described, we've specifically engineered suitable pharmaceutical properties into its creation. It is orally bioavailable, and we specifically designed a PK profile that mimics the sleep-wake cycle and is designed to improve, support, improve daytime wakefulness with single daily dosing. And because of our positive data in our 1b study in patients, including safety, efficacy, and PK, we have moved quickly and efficiently into phase 2 with a high degree of confidence in our chosen doses. And I know Bhaskar will walk you through this data later this morning.... This slide shows the trial design used in our phase 1b proof of concept study, which was key in informing our phase 2 design and our dose levels. This is a highly efficient design. It used a four-way crossover design, which permitted the testing of three different doses of ALKS 2680 and placebo in every patient enrolled. This crossover design was an important attribute that led to our phase 2 dose selection, as it allowed for each patient to serve as their own control, thus reducing and mitigating the types of inter-patient variability that is commonly seen in clinical trials. Our patient population had to meet the ICSD criteria for their respective disorders. However, eligibility criteria did not mandate baseline maintenance of wakefulness testing results, so the variability was consistent with what one would expect in real world, in the real-world setting. The objectives included safety, efficacy, as measured by the Maintenance of Wakefulness Test. Let's move to the data, starting with safety. Principally, the key objective in a phase I program is to identify any early safety signals. ALKS 2680 showed itself to be generally safe and well-tolerated at all doses tested in NT1, NT2, and IH. Nearly all of the adverse events observed were transient and mild in severity, and in clinical trials, the designation of mild actually is firmly defined in the protocols. It means that while the adverse event was noted, it was tolerable and did not interfere with acts of daily living. There were no serious and no severe AEs, and no AEs leading to early treatment discontinuation. The most common AEs in each population that were considered treatment-related are listed here, but principally included insomnia, polyuria, and dizziness. Importantly, there were no clinically meaningful trends or results or findings in laboratory values, in vital signs, in ECGs. There was no evidence of a cardiovascular safety signal. This slide provides the results of our primary efficacy outcome, the mean sleep latency, which is essentially how long patients can resist falling asleep during the maintenance of wakefulness test, which is a forty-minute test. ALKS 2680 demonstrated clinically meaningful and statistically significant improvements from baseline in mean sleep latency compared with placebo at all doses across all indications. The graphs that we show here include the observed or the absolute mean sleep latency, and below the graphs, we've provided the primary efficacy analysis, the least square mean difference in sleep latency versus placebo. You can see from that analysis that at each dose, dose tested in all indications were highly statistically significant. I think it's important, though, in presenting the data in this aggregated form, that there are some key takeaways I'd like to leave you with. First of all, ALKS 2680 improved mean sleep latency in all patient populations, and this is important because it's irrespective of the underlying orexin levels in these different conditions. Secondly, as I mentioned, the results were statistically significant and clinically meaningful. What's but what's really notable is the consistency of this result, irrespective of the variability at baseline assessments. Finally, the dose-dependent and clinically meaningful improvements in wakefulness that resulted in patients achieving mean wakefulness levels of normal individuals, normal healthy individuals that typically have sleep latencies of 30 minutes plus or minus 10. It's these data that give us great confidence to move into phase 2. It's the consistency, it's the magnitude of the effect, and it is the efficacy, efficacy that we're observing in patients who endogenously produce orexin and those who do not. Let's move forward. In summary, we are ready to move into phase 2 based on the data we've showed you so far. The safety profile shows that ALKS 2680 is generally safe and well-tolerated, and as I described to you, the efficacy shows consistency, shows a high magnitude of effect, and it shows it works across three different indications, as I described. Now I'm going to take you through the designs of our phase 2 studies. We have two phase 2 studies ongoing, Vibrance-1 in patients with NT1 and Vibrance-2 in patients with NT2. These studies share some of the same design features. Both studies have a double-blind treatment period where we will be comparing three different dose levels against placebo for a period of time, and then all patients will roll into an open label extension, where there will be an adjustment of dose. All patients will begin at the mid dose level of six mg... Depending on the trial, they'll begin at a mid dose level, and then we'll be able to adjust that dose. And this is a unique feature of the study that we believe is going to yield some very important information in terms of patient preferences that we will then use and build into our phase 3 program. This table gives some additional details and points I'd like to emphasize. Across these two studies, we are exploring a range of doses, and the ability to dose adjust in the open-label extension is a unique and differentiating feature of this program. We are also in the process of opening a long-term, open-label extension study. In the very near future, the patients will be able to roll into and continue to receive ALKS 2680. In addition to these two phase 2 studies I've described here, we are in the design phases of Vibrance-3, which will be a phase 2 study in patients with IH, and we plan to initiate this next year. I just want to pause here and emphasize that these are serious diseases, and they impact so many aspects of patients' lives and their families' lives. As you'll hear from Charlie next, the impact of these disorders far exceeds what can be measured in the sleep lab. Hence, we designed our phase 2 program to collect data to support the profile of ALKS 2680, both in terms of classic symptoms, registrational outcomes, as well as those symptoms and outcomes that are important to patients. We're doing this using validated scales, including sleep quality, cognition, fatigue, and the ability to engage in daily activities and the impact on relationships. In my experience across multiple therapeutic areas, including rare diseases, the success in organizing and executing clinical trials is enabled by the quality of the data supporting the potential medicine. The more information we can share with our clinical researchers regarding the safety, the tolerability, the efficacy of an experimental agent, the better they are to determine whether or not they'd like to offer this to their patients that they take care of as an option. With the data that we presented at major medical meetings by key thought leaders associated with this program, a generally well-tolerated protocol profile has been demonstrated across a range of patient types, and we have shown some exciting efficacy signals. So we believe we have all the elements in place as we accelerate our program into later-stage development. Our investigators are very enthusiastic based on the data we've generated in our phase 1b program, and we are building momentum in phase 2. Thus, with an intense focus on execution, we expect to have the data from Vibrance-1 and Vibrance-2 sometime in the second half of next year. And in parallel with conducting our phase 2, we are preparing for success and doing the foundational work to plan for our potential phase 3 program. So we're in strong position, and we're looking forward to updating you in the future. So now I'd like to welcome Charlie Peck to the podium. Thank you, everyone. There you go. Thank you, Julie. My name is Charlie Peck. I head up new product planning here at Alkermes, and I look forward to sharing with you the insights that we've gathered around narcolepsy and IH as it pertains to both prevalence and the experiences that people living with these conditions have. Now, as we deepened our understanding of these patients, there were a couple of non-obvious insights that we gathered. One around prevalence as it relates to the prevalence of NT1 and NT2, and also perhaps a discrepancy between the view of unmet needs coming from treating physicians as well as patients. The reason why we are looking at this is to better inform ourselves as Alkermes in terms of the how and the why of developing drugs for these conditions. Let's turn to prevalence. Unfortunately, narcolepsy and IH affect people around the world. For today's session, I'd like to focus in on the U.S., both for the patient experiences and the prevalence. Having said that, we have conducted primary research with patients outside of the U.S., and unfortunately, the experiences that they have are also uniform across the different regions. And as far as the prevalence goes, again, I will focus in on the U.S., but these can be scaled to the rest of the world. There are about approximately two hundred thousand overall prevalence narcolepsy patients, of which a hundred thousand are diagnosed. Now, that simple statistic, that 50% diagnosis rate, really doesn't do justice to the patient journey. It can take ten, fifteen years between exhibiting the first symptoms to actually receiving the diagnosis of narcolepsy, which really talks to some of the challenges that Julie had hinted at about getting there. It's our thought that greater awareness of this condition, greater availability of novel therapies, may increase the diagnosis rate, which of course, in turn, can improve and increase the treatable patient pool. Now, in addition to the narcolepsy patients, there are forty thousand diagnosed IH patients, and again, this is another area of diagnostic confusion between IH and narcolepsy. Again, given some of the overlap that Julie had talked about in terms of the symptomatology. Another area of diagnostic challenge relates to the prevalence between narcolepsy type one and narcolepsy type two. Now, earlier studies suggested that there were more NT one patients than NT two, and these are in the Silber and Longstreth. Both of these are based on medical records coming from single counties and single states, so Minnesota and Washington, and these suggested that perhaps it's a two to one ratio of NT one to NT two. However, the understanding is evolving over time, and if you look at the later publications, looking at a variety of methodological approaches, they suggest that there are actually more NT two patients than NT one, so Cohen et al. also adopted an audited medical record approach, however, with updated ICSD-3 diagnostic criteria. There was also a claims-based approach presented in Scheer and also internal work that we had done. And then yet again, another approach in Ohayon, where they looked at prospective surveys that were sent out to residents of fifteen states in the U.S. Despite the commonalities, despite the different approaches, the commonality is that they all suggest there are more NT2 than NT1 patients, approximately a one to two ratio. Now, regardless of the prevalence of NT1 to NT2, what we know and what I'll share to you is the unmet need that's present in all of these patients. And it's our belief that any therapy that's indicated for the treatment of both type one and type two would be a welcome addition. There are, as you know, drugs approved for the treatment of narcolepsy. Some of these approved more than twenty years ago, and the net sales across these different therapies generated over $2.5 billion. Now, given the availability of these therapies, we were interested to understand what is the current satisfaction levels by physicians, the treating physicians, with these available therapies, so we conducted primary market research with treating physicians and asked them on a ten-point scale of satisfaction, so one represents completely unsatisfied with the current therapies, ten representing I am fully satisfied with the therapies that are available today. On average, the treating physician gives it about a six, so middle of the road, and this is not what we hear from the patients, as I'll share. There's no ambiguity from what we've heard from the patients in terms of their satisfaction levels, so let's turn to that. I think at a high level, the overall unmet need is well illustrated with a survey conducted with over a thousand patients with narcolepsy, summarized in this review article. Almost all of them had been previously treated with at least one of these approved therapies, and despite that, the majority of them complained of daily narcolepsy symptoms, 34%. And an even greater proportion talked about the negative impact that it has on their work, on their school performance, 84%. So this high level view really caused us to want to understand this at a deeper level and individual patient level, and so we conducted primary market research with narcolepsy and IH patients. And what we've learned from that really is well captured under the construct of Maslow's hierarchy of needs. As a reminder, this is a hierarchy of needs that was described that is relevant for all of us. As human beings, that we all have needs, and these can be classified into lower order needs that need to be met and addressed for us to think about these higher order needs. These lower order needs are foundational needs, the need for well-regulated sleep, just as important as the need for water, air, shelter. If these needs aren't met, we don't have the opportunity to think about the higher order needs of: How do we actually fit in with society? How do we interact with friends and family? What is it that I want to be? And the opportunity to actually self-actualize and achieve those goals. And unfortunately, what we've heard from narcolepsy and IH patients is that they have to focus their energies on these foundational needs, and they avoid, quote, "wasting energy on higher order needs." And really, what brought it home was one example, one analogy that one of the narcolepsy patients had mentioned, and he talked about it analogous to your phone. So at the end of the day, if you're like me, you plug in your phone, and then you wake up, unplug, and you have a 100% charge. You're fully in the green. And this patient talked about when he wakes up, he does not start with a 100% charge. He starts the day in the red and having to adapt to that on a daily basis. And that adaptation on a daily basis means: When am I going to be able to take a nap? 'Cause I have to do this. Am I going to actually interact with friends? How am I going to interact with family? And this daily struggle, unfortunately, extends into longer term, where it actually talks about what sort of job choices can I make? Should I pursue higher education? Can I have a relationship? Should I get married? Should I have children? Who's going to take care of the children? And this is an ongoing struggle. When we ask the patients, "What is the impact of the symptoms, and how does it affect your lives?" They talk about the impact on their safety, productivity, mental health, and their relationships. And I think what really brings it home is to actually hear it from the patient's words. And under safety, one example, this narcolepsy patient talked about, "I was at work one day. I fell asleep holding a piece of industrial glass, and I dropped it and almost cut my artery in my neck." On productivity, this was a patient recalling back to when she was in school. "I used to fall asleep in class all the time, and then everyone would get upset. I would end up in detention for sleeping in class. I would try so hard to stay awake. Everyone just thought I didn't care enough to stay awake." And you can imagine the toll that this takes on their mental health. "I felt inadequate. I had low self-esteem due to not having the energy to do basic things my peers did, and lonely because I would spend so much time on my own sleeping."... As far as relationships, this was coming from a mother who was on vacation at the beach. I don't feel comfortable taking my son or my foster son on vacation alone, because sometimes I have to sleep. I can't not sleep. So we're at the beach, and I have to bring somebody with me so that I can make sure the children are safe." So when we ask these patients, "What are the areas of unmet needs? What is it that you would like to have addressed?" They talk about getting better symptom control. They talk about having a disease-modifying therapy that is not a stimulant. For symptom control, I would be alert. I wouldn't constantly feel like I need to take a nap despite all the treatments I'm taking. Disease-modifying: I wish there was an option for my sleep disorder that could treat the cause and not just the symptoms. It would allow my body to do what it should be able to do on its own. And on stimulants, I'm fearful that I'm hurting my body or that I'll lash out at people. It's scary being on something that's so strictly controlled. I can't really trust stimulants to help me. So in closing, I want to take us back to a comment that I made at the start, is why are we looking at this? Why are we looking at patient insights? And it's our belief here at Alkermes, that understanding the patient experience and instilling it into our development program is just as important as understanding the science that underlies narcolepsy that Brian talked about. It's just as important as clinical outcomes, regulatory considerations, and we intend on weaving all of these together into our clinical development program, into our clinical trial design, with the aspiration that we will be able to generate a therapy that meaningfully addresses the needs of the patients. Thank you. And with that, I'll turn it over to Sandy. I'll ask our thought leaders to join me at the front here. I should have mentioned it at the beginning, but there is an opportunity to submit questions via the webcast viewer for folks viewing from their computers at home, but I also invite the folks in the room to join in the discussion. I'm delighted today to be joined by Dr. David Plante from the University of Wisconsin-Madison, and Dr. Kiran Maski from Boston Children's, and Monica Gow, who is a co-founder of Wake Up Narcolepsy, and they're here to share with us their clinician point of view and also their lived experience dealing with these serious diseases. So maybe just to warm up and start the conversation, I invite all of you to, based on your experience, provide some context on what the current unmet needs are for patients with narcolepsy and IH. You want to go first? Yeah, I think the major thing that people are dealing with is lack of efficacy, as kind of shown here, in some of the slides. It seems very consistent with the reality of what people are experiencing, where they're operating at maybe a six out of 10. And so they're making decisions all the time about how to prioritize, you know, work, school, how to balance that. And I work with a younger population of patients, so children up to age, all the way up to age 25. And so it is interesting to see what kind of has to be left out of those calculations, and oftentimes, it's social consequences. So they're, you know, prioritizing school and early work, but don't have the bandwidth to form relationships or hang out with friends in a meaningful way. And then I think from the survey that was highlighted here, the Patient Voice Survey, other details seem really clinically relevant, so lifestyle factors of taking the medications. So medications such as oxybate really take quite a bit of planning. You know, you have to have a regular amount of sleep, you can't drink alcohol, you can't take any sedating substances, and if you think about young adults, like that's, you know, sleep irregularities, socializing with friends with alcohol is a big part of culture, and so they feel sort of shut out from that. And I think other things are, you know, having to redose medications through the day sometimes gets onerous, especially for younger populations. They have to go to the nurse's station or something like that in the middle of the day to get a second dose. Then side effects, I think, is the other big thing. You know, I think, people struggle with a high degree of side effects with the current therapies, so things like insomnia are common, but more issues related to headache actually are big problems for us, as well as cardiovascular issues, which I think is getting more attention these days from the literature. That's excellent. Monica, since your son was diagnosed when he was a child and is now an adult, and maybe you can provide some perspective on Dr. Maski's comments and add what you think the patients are still where the unmet need is. Mm-hmm. Sure. In addition to what Dr. Maski said, I think getting people diagnosed early is key to having a productive life while trying to manage narcolepsy. We were fortunate. My son was diagnosed within three months, and we learned that people, you know, once we-- the reason we started Wake Up Narcolepsy is what we learned after, we found this out on, you know, we, of course, we turned to the website, to the internet to find out what was happening in the space, and not much was happening at that time. That was two thousand and eight. So I think the early diagnosis is key. Finding the right doctor who knows what they're doing and how to prescribe the medicine is key. Also-... A lot of the sleep doctors are focused on sleep apnea, and not all of them are knowledgeable in narcolepsy. Then also finding that community where they can be accepted. We hear so often that people go years and years without meeting someone in person who has narcolepsy, so we try to, you know, have community events to get people together to just talk and meet someone else who's going through what they're going through. A lot of the stigma, too, can be reduced with awareness and education. You know, people are embarrassed. They don't want to talk about their narcolepsy, especially to employers who would not understand the need to sleep. I just see it as this sleep is the thing that is so prominent, and you're a person with narcolepsy, from what I see, is you're just always managing that. When am I going to nap again? When am I going to go to school and stay there all day? Like, where am I going to strategically nap? We used to when my son was in middle school, I would show up in the parking lot so he could run out and nap and then go to, like, the Halloween party or whatever was happening, so. But not every child has that, so you just have to, you know, provide support as a family. Maybe, Dr. Plante, can you talk through some of the challenges that you face when diagnosing, NT1 versus NT2 or IH? Sure. So it's-- And I would just echo what's been said so far. I mean, I think most of the treatments are kind of like Band-Aids. Like, they kind of help people get through the day, but they don't sort of oftentimes, especially in the case of Narcolepsy Type 1, treat the underlying problem. In terms of the differential diagnosis of NT1 versus NT2, that's challenging. All of these diagnoses really hinge on a very complicated in-laboratory set of testing called the polysomnogram and Multiple Sleep Latency Test, or MSLT, where people have to spend basically 24 hours in the sleep lab with an overnight of sleep and then multiple repeated naps across the course of the day. We're really distinguishing these disorders using those tests to see how quickly people fall asleep on the naps, and also if they go into early onset REMs, which is a marker of narcolepsy. In the case of NT1, though, we know that it's caused by fundamentally orexin deficiency. There's also another way to make the diagnosis, which is with a lumbar puncture. That's challenging because a lot of patients aren't super excited about doing a lumbar puncture, and also, up until relatively recently, it was hard to actually measure that value in a laboratory. You either had to be at a special academic institution, but now you can send it away to Mayo. So there's challenges in terms of, like, just access to the testing for a lot of people. There's a challenge of recognition. You can't make a diagnosis if you don't think about it in the first place, and a lot of providers, I think, out in the community, aren't necessarily thinking about narcolepsy sort of being kind of up on a differential. And then oftentimes, people, by the time they get to us in clinic, in sleep clinics, that are a specialty, they've been treated with a number of different medications for other processes, so comorbid depression and things like that. That will impact our ability to use our standard sleep tests. So we will not be able to oftentimes detect early onset REM periods if people are on an antidepressant medication. So even just sort of where people come to us can make it challenging based on sort of a number of different factors. I guess the final thing that I'll say is, not everyone manifests with cataplexy who has type 1 narcolepsy. This is another challenge in our field. Cataplexy, which is the loss of muscle tone in response to emotional stimuli, classically, laughter or mirth, is a very specific symptom of narcolepsy. When, as clinicians, we hear that in combination with excessive daytime sleepiness, we automatically gravitate to the thought that this, this person may have type 1 narcolepsy. It turns out, though, about 20% of people who meet criteria for narcolepsy, so have type 2 narcolepsy, don't have cataplexy. They don't complain about this clinically, even when you ask them. It turns out, when you do a lumbar puncture, 20% of those folks will actually have NT1, so they'll have an orexin deficiency. Even identifying the pathology based on clinical presentation can be very challenging as well. Okay. In the room? Okay, Joe, please. You mentioned earlier the... Sorry, Joseph Thome- Hold on one sec. We'll get you a mic, and then we can web-- we can be on the webcast, too. Hi, there. Joseph Thome from TD Cowen. Thank you for taking my question. You mentioned earlier the lack of efficacy of current available agents. I guess when you look at the MWT, is there a sweet spot for efficacy on that? Because obviously, the orexin class is getting towards the end of the scale. And the company mentioned the opportunity for flexible dosing. Is that when you would use flexible dosing, or how do you incorporate that? Yeah, I think the MWT question's really good. I was on the practice parameters for the treatments of CNS disorders of hypersomnolence, and so we looked at the MWT as sort of, you know, an objective gold standard measure. Interestingly, compared to sort of... If you look at the classes across all of, all of the narcolepsy therapies, they really range anywhere from, like, one minute to maybe up to, like, 6, 7 minutes, maybe maximum 12 minutes, in terms of, you know, the total mean sleep latency improvement. So the threshold of clinical, you know, a meaningful improvement, we had to set it very low. Otherwise, we would have had no medications really to evaluate. So the MCID is only two minutes. So when you're looking at these orexin class drugs, you know, this is really exciting for us to, to be seeing these numbers. And then to the flexibility question, I think, you know, I do see more heterogeneity about that, that particular need. So some people, you know, I think most people, I would argue, want to take a single medication that lasts through the day. But some people do benefit from taking naps or things like that, and, you know, like the flexibility of taking a nap, then taking a second dose after. So there is some variability in the field about that, but I would say, you know, the, the majority of working and school-aged people, once a day would be helpful. ... Right. Marc Goodman from Leerink Partners. I was hoping that each of the physicians could describe how many patients they treat, and how many are NT one, how many are NT two, how many are IH, and whether the diagnosis changed over time. And we're trying to fast forward, you know, four or five, whenever these orexins are on the market, if there's an orexin that's only for NT one, but then you have an orexin that's for all of narcolepsy, how much that's gonna matter, and if you only have one of them versus the other? You know, we're trying to gauge like, how this whole competitive dynamic is gonna matter, too, by having a full narcolepsy indication versus just NT one. Thank you. So, I guess I can start without having the EMR open in front of me and looking at the lists of. You know, I think that. And also, please keep in mind that my practice is probably gonna be a little bit biased just because of my sort of area of expertise and also the people who might seek me out. So, I probably, I think it's about fifty/fifty in terms of NT one and NT two, and then for me, I have about double that in terms of IH patients. But again, I'm not sure that you can extrapolate that out to the general population. In terms of sort of your other question about like sort of the specificity of an orexin agonist related to diagnosis, I mean, I think that if you have NT1, you know that it's an orexin deficiency, so you're basically treating directly sort of the fundamental problem. You know, these other disorders, I think we don't know what causes NT2, we don't know what causes IH fundamentally. So the question is, like, what's the best treatment option? We know that probably people are gonna need different doses, right, if they don't have an orexin deficiency. So I think that will affect the potential choice of agent. But then also having the ability to try different agents is really important as well. If a drug is only approved for one type of narcolepsy, then we'll have to be very careful and can only use it in a limited number of people at a limited dose range. Before we go to the next question in the room, Monica, can you give us a sense of how aware patients are of new drugs and development and the research that's being done in this space? I would say there are many different variances that would go into that. One would be the relationship they may have with their physician, and then the physician's knowledge of what's going on in this space with clinical trials, to their financial you know, ability and their geographic location definitely would play a role. I would also say whether or not they're connected with any patient advocate organizations that share this type of information, and also, lastly, just their interaction with people on social media, which is where they learn and gather a lot of their information, depends on those four things, I would say. That's really helpful. Thank you. Thanks. David Amsellem at Piper Sandler, so I wanted to ask a question about safety and tolerability of the clinicians up on stage, so in the Phase I-B studies, a couple of the AEs that were identified, one was visual disturbances, the other was daytime urinary urgency. And I was hoping you could contextualize those AEs, the extent to which you're concerned about them. Help us understand how to think about those kind of AEs in the context of the other treatments that are available, such as the oxybates, or stimulants or modafinil, and help us understand, you know, how you're thinking about the body of safety tolerability data for 2680 in terms of what we've seen thus far, relative to what you're currently using for your patients. Thank you. I can start. I mean, I think currently with side effects of the medications we're seeing, it is probably around 30%-80% of AEs, and the more common side effects are increase in mood disturbances to the point of suicidality, and hypertension, so increases in blood pressure, and then headaches, appetite suppression, weight loss. I would say those are sort of the big five for us. So the side effects with the oxybate class, and David can chime in, are relatively new for us. You know, things like increased urinary urgency, hypersalivation, I think are not something that we're encountering. Visual disturbance also. I mean, frankly, I talk to my patients about, you know, anything that comes out in the literature about orexin agonists, and I've mentioned the urinary urgency. It does not seem to bother them when they really talk about the benefit of what, you know, the wakefulness component are. I mean, anecdotally, I have a couple of patients who were like: "That's not a problem. I drink cold water all through the day anyway." Like, "I'm going to the bathroom already a lot." I think it is the magnitude of what the results are in a larger study, though, that might impact that. The visual disturbance, I think, is concerning. I mean, I think anyone who has visual disturbance that's affecting their ability to perform or drive is gonna be of concern, and that's something that now obviously needs to be evaluated in a larger study. But we were. I think looking at the published data doesn't really suggest that that's a big concern at this point, but I agree it has to be watched. Yeah, I mean, I would just build on that, and I think you have to take sort of the data that's available currently, like in context, right? So that study, people were given a specific dose, were very tightly monitored, sort of in a sort of very careful setting for a full twenty-four hours. The report of sort of what may be a, a side effect when you're out in the world taking medication on your day-to-day life may be very different. That said, my understanding, too, about the, the visual disturbances, we weren't a study site, so I would defer to the company. And all this is that really, those occurred at, at higher doses. They were short-lived, transient, and didn't require any specific treatment. And I do think that also for the Vibrance-1 and 2 studies, there is, like, an ophthalmology examination as part of the protocol. So we kind of really keep a close eye on that because obviously, that would be a concern. In terms of polyuria, I agree. I think that most patients would see it as that that would be worthwhile of a trade-off, right? And the other thing is we don't know how it's gonna play out over time, because, again, in the early study, it was, you know, transitory administration, watch for twenty-four hours. We don't know if it's something that people sort of equilibrate to over time. Okay. Joel Beatty from Baird. In a slide earlier today, we saw that oxybates seemed to be the best-selling class for narcolepsy and IH. If the ALKS 2680 data looks as it does so far, how would you decide between using oxybates and ALKS 2680, and would there be some patients that you might use both in? I mean, in terms of like, I'll get to the last question first, because it's easy. Are there some patients who may need both? Potentially, yeah. So it really depends on the person's clinical situation. We use polypharmacy quite frequently in these disorders. I think it would depend a little bit on how sort of an orexin agonist, since it would be dosed during the day, affects sleep, and I think that is a kind of an open area for trying to understand big picture, what that's going to look like. In terms of like, would I choose one over the other? I mean, I think that you would look first at efficacy data, sort of once these sort of things move through the pipeline, and have also a sense of like, what the person's diagnosis is. I mean, I think for NT one, it's pretty straightforward that probably an orexin agonist would make by far and away the most sense, because again, you're targeting the fundamental pathology. For NT two, for IH, it's a little bit less clear. The phenotypes can get a little bit more complicated in those disorders. And we don't really know exactly how that's going to play out in terms of like, things like long sleep time, excessive sleep inertia, and some of those other symptoms that come up, especially more in the IH phenotype. So I think it'd really depend on sort of how people do with the medication in these studies. Yeah, thank you for the time today. In the real world, I guess, could you explain how, if at all, you really differentiate between NT2s versus the IH patients? You know, I think sometimes they come into your practice already having been maybe diagnosed, maybe not diagnosed, maybe just saying they were often sleepy, as opposed to really knowing underlying REM patterns or things like that. How squishy is that label, in your opinion? And I guess- David, take that. How does it matter, if at all, kind of that delineation? That's a great question, and I'm happy to talk a lot with you, too, about it. So, the difference between NT two and IH is really complicated, and there's a lot of factors that go into it. You know, fundamentally, these are disorders of excessive daytime sleepiness that we don't know the cause of it, except for that sort of 20% of people with NT two, right, who actually have NT one, who get miscategorized because we usually aren't getting a lumbar puncture on these folks. So, when you use the word real world, I have to keep in mind that my practice is probably not the real world, right? Because I'm doing something probably a little bit different, being in an academic center and thinking about these things, you know, pretty deeply. You know, some of the things that I will do are use things like HLA-DQB1*0602 testing in people who don't have cataplexy when it's important, because we know from the data that if you don't have cataplexy and you don't have this HLA allele, it puts you at risk for having narcolepsy in the first place, then you don't have NT1, right? So you can use some other sort of pieces of data to move people into sort of probabilistic diagnostic categories, to, to put it in a different way. So there's... In terms of like, what the, the fundamental difference is between people with NT2 and IH, it's, it's complicated. Even within the field, there is some discussion about whether or not these diagnostic constructs should be merged at some level. Probably people who sleep long amounts of time, who have IH, are probably a little bit different than people who don't sleep long amounts of time. So it's a complicated issue, to say the least. I can also chime in. I mean, I think for research purposes, we're always trying to have practical implementations as well. So, we use scales like the Idiopathic Hypersomnia Scale, which really has domains of long sleep duration, sleep inertia, as well as daytime sleepiness. And the majority, I want to say, like 70% of idiopathic hypersomnia patients do have a longer sleep phenotype, this real difficulty getting up in the morning. And those seem to be, they're overlapping, but sort of distinguishing in the magnitude of severity of those symptoms, so that scale is helpful. And then, while it may not be as real world, we're trying to implement protocols where essentially that long sleep duration is actually captured on the polysomnogram, and then an MSLT is done, so we can kinda capture both symptomology. I think that's clinically feasible for other groups, but they want us to test it out first. And one real-world thing I want to also mention, in terms of thinking about some of the data that were presented in terms of like NT two is, a lot of times people end up in our clinic who have been seen elsewhere, diagnosed with type two narcolepsy. Sometimes that diagnosis is made by a well-meaning physician because historically, the drugs have always been approved to treat narcolepsy. And people with IH, for a long time, were kind of stuck with no options that were approved to treat them. So sometimes people would say, "Well, you're sleepy enough on the sleep study. You seem like you have narcolepsy, so I'm gonna give you a diagnosis of narcolepsy." So I always take all the claims data with a big grain of salt based on, you know, some of those sort of... where the rubber meets the road of clinical care, I guess is what I'd put out there, too. And then just one follow-up. How much does cost of the medicine come into play? You obviously have, for NT2s or IH patients, you have two options or three options: cheap things like Adderall and or Adderall XR and Provigil, that are very inexpensive, if not almost free, and largely safe. And then oxybate, which is not free at all, but approved. Some have even said that it's actually easier to get oxybate approved in IH than NT 2. Would you agree with those statements? And I guess, to what extent does it matter, the cost of the medicine in either of those two buckets? Thank you. I mean, I think in the U.S. system, we're using payers, insurance payers, and the contracts that are going on between pharmacy benefit managers and the companies and, you know, is something that is more black box and opaque at my level. So yes, we've had that experience of, you know, an oxybate is actually easier to get than a stimulant, even independent of cost, because it's FDA-approved and whatever contracts are behind the scenes are happening. So that is, that is true, but for narcolepsy, at least in this state of Massachusetts, you know, payers have different step therapy, and so oftentimes you do need to fail like one or two traditional stimulants, then you get to the next class, and you get to the next class. Whether that would change with like, you know, such robust efficacy data, I think would be helpful. You know, and I don't know where practice parameters will fit into that versus expert consensus. Monica, I'd love to get your perspective on that from the patient groups. How much does cost play into treatment decisions, and are there significant challenges there that patients have? It has an impact, a very high impact on what people are able to use for their medication. You know, a lot of people with narcolepsy are on disability, so they don't have insurance. Some of the pharmaceutical companies do have programs where they assist with the payment of, you know, of the medication, but it's definitely a huge impact. Just for the real world, Narcolepsy Type 2 and IH, the patients are so confused because they're back and forth, doctors telling them they have IH and Narcolepsy Type 2. So there's so much confusion inside the patient's head and what's going on in the community. That's really helpful. Okay. Hi, thanks. This is Qi for Jason Gerberry at BoFA. I've a couple of follow-up questions. I guess the first one is, what we've heard is that physicians care about the quality of wakefulness as much as the quantity of the wakefulness. I'm curious, in practice, is there any scale that you would use to monitor the quality of wakefulness? And is there anything that you would look for, either a standardized test or a new test, that you would hope to see in clinical trial to help inform the therapeutic potential of the orexin class in this aspect? Yeah. Yeah, so I mean, clinically, the most common scale that's gonna be used to assess sort of daytime sleepiness is going to be the Epworth Sleepiness Scale. Now, the challenge with the Epworth Sleepiness Scale is that it's a very sort of cursory scale. It measures your likelihood to doze under real or imagined situations in eight possible opportunities, like, eight situations, and it's scaled zero to three, and then you just add it up. So it's very simple, and it's useful in sleep medicine, and it's sort of applicable to a bunch of different disorders. So that's why everybody gets it. The challenges with these types of disorders, a lot of times, even with the medication, sometimes people can doze if they let themselves pretty easily. So even if they're actually saying, "I'm, Doc, you know, Doc, I'm actually doing really well, I'm feeling pretty good," they may have an elevated Epworth scale. You have to move way beyond just, like, these basic symptom scales, and I think really get at quality-of-life measures, I think is really what's most important based on some of the things that have already been discussed today and what people experience. I think we spend a lot of time really focusing on, like, how awake and alert are you, whereas realistically, that may not be the thing that really impacts people. It's usually function and those kind of downstream things. I mean, I think I would just add to that, that no, there is no scale, that's been talked about, you know, that we have four sleep stages, how come we don't have, like, differentiation of wakefulness in a similar type way? But I think that some of the features of, like, good wakefulness, if you will, relate to cognition. So it is really encouraging to see new clinical trials implement cognitive outcomes. Things relating to alertness and focus, I think, kind of go hand in hand with a good quality of wakefulness. And I've got a question from Charles Duncan at Cantor Fitzgerald. For the Vibrance-1 and Vibrance-2 trials, how do you see even mild AEs such as insomnia, dizziness, and polyuria impacting effect size? Are you concerned about these potential confounding variables due to study design or sample size, reducing your risk or data interpretation? And sorry, that should have been: Are you not concerned about these confounding variables? Oh, sorry, what are the confounding variables? The question is: Are you concerned that even mild AEs may have functional unblinding on the study? Oh. and would you expect that to impact effect size? Well, so I think that there's always the risk of unblinding with any compound that is highly effective, right? Especially if people are on a placebo, and I think that would go for any, you know, potential study design. I mean, I think that one of the reasons that things like the MWT are used, too, is that there's less of a placebo effect with the MWT than some of these other sort of purely self-administered scales. So that's kind of how I would look at it. Yeah. That's why the MWT and subjective report are both important. ... Okay. Do we have any more questions from the room? One more. Hi, Mark Hetrick from Stifel. Just a few questions about, you know, the treatment paradigms in your practice. So, you know, out of the patients sort of that are diagnosed in your practice, what would you say the percent that gets treated? And then sort of just to piggyback on that, like, what's the refractory group? Like, what patients tried the drugs and that don't end up working, have to drop it. And then also just wanted to get an idea, those that are on the therapy, like, what's the sense of urgency to, like, try something new? Like, they're currently on oxybates or the stimulants, and they're really, like, trying to get a sense of the new therapies that are out there. Are they brand loyal, are going to stay? And then is there any difference across the indications, NT one, NT two, and IH? Thank you. I'll start. I mean, I think that, yes, so there's a lot of excitement for these orexin classes because it's a very specific therapy for the problem that they have. Because most of our patients, as David mentioned, are on polypharmacy, and there is this feeling like the runway is ending. You know, they're on all these medications, and they're still at a level six. So this, the development of these compounds is coming at, like, a really, I think, important time, and I'm sorry, what was the second question again? Yeah, sorry. So, so, like, out of the patients that are in your practice, like the ones that are diagnosed, what percent are actually getting treated? So, like, what's that group that's like- Oh. Maybe not on therapy, they tried it, it didn't work, they had to go off. Got it. I think, I want to say, like, 95%- Okay ... start and stay on therapy, and then it's adding additional, you know, therapy. Things like oxybate are probably our highest side effect profile medications. That's the one that comes to mind when people are coming off medications, and that might be for lifestyle reasons, that might be from side effects, like nocturnal enuresis is a common reason, or nocturnal eating. But, you know, sometimes it's, if it's a lifestyle issue, they might want to restart it in a couple of years. But I would say most of them are on pretty stable medication. So I would say, sort of piggybacking on that, so the folks in my practice that tend to be most refractory, again, some of this may have to do with my referral patterns, are folks with idiopathic hypersomnia, especially folks who have long sleep time. I think typically they're a little bit harder to treat than other folks. I would say in terms of, like, regardless of what people are taking, like, you know, a lot of times we get to a steady state where we found what works best for people, and even if there is something that's new, that's out there, when I talk to a patient, a lot of times they're like: "I don't want to make any changes." And that's because they've kind of reached this equilibrium in their life where they can get to work, they can do what they need to do. They're not doing their best, but they're doing okay, right? They're getting by, and they don't see, like... They see kind of these next things as probably marginal gains to their symptoms and so they don't really want to upset the apple cart just to see if they can get a marginal gain. But when I talk to patients about these medications coming out or coming down the pipe, their ears perk up, and they are much more interested in them than they have been sort of in other sort of areas that are just, again, sort of pushing the same kind of direction. So that's my experience for what it's worth. Yeah. Thank you, and just one follow-up question. So in the first year, let's imagine these orexins get launched, what percent of your practice would you envision, switching over within that first year to this novel, mechanism? So for NT1 or- Or across the- I mean, what I would say, probably for NT1, it would probably be very high, like 95% or more would be interested in wanting to at least try the medication, whether it worked for them or tolerate. I, but I think for the other groups, I think it depends on how they're doing, you know, in terms of their overall treatment. So probably I would say that would be lower. My guess would probably be about, of my practice, maybe 25% or something, but that's a rough estimate. I would agree. I would say the majority of the NT1 patients would wanna switch over. I think I would say 50%, maybe higher, of the narcolepsy type 2. Remember, they have less options currently. You know, they're. They might not receive as much benefit from oxybate because they don't have as much disrupted nighttime sleep. So usually it's stimulants, modafinil, solriamfetol, pitolisant, and so they've kind of run out of options. And so if those aren't working, you know, looking at the data, you know, seems to be much more efficacious. Similar for the IH population. I think even more so, they fail stimulants and wake-promoting medications. So I could imagine that being a group, which I will also add, is our largest group growing in terms of diagnoses, most interested in this group. So maybe that group, I'd put even higher of 60%. Thank you. Okay, I'm going to try to keep us on track here. So we're going to conclude this portion of the roundtable panel. We are, Dr. Maski and Dr. Plante will be sticking with us for the remainder of the event, so they'll be around for additional questions later on. But I just want to express my sincere appreciation to all three of you, and Monica, thank you for sharing your family's experience and the work that Wake Up Narcolepsy is doing. It's an excellent resource, even for non-patient communities, so to learn more about the space, speaking from personal experience. Thank you again, and we'll move on to our next presenter, Bhaskar Rege. Firstly, I'd like to thank all the panel of experts for such a valuable insights. The insights like these we hear from clinicians as well as patients really inform the way we develop medicines. It not only help us to design our target product profile here, but also establish efficacy and safety thresholds that guide our development. The foundation of decision-making it's during the development is based on rigorous data collection and analysis in order to achieve these profiles. Now, before I dive into this, let me first introduce myself. My name is Bhaskar Rege, and I lead the orexin program at Alkermes. I have a Ph.D. in clinical pharmacology, and I've, during my career, I've been involved in development and approval of nine different drugs, mainly in the field of neuroscience. And over the several years, I've developed a special interest and expertise in complex biostatistical, pharmacokinetic, and pharmacodynamic modeling and methods for early translational and experimental medicine studies, in the clinic. And all of this experience is being brought to bear in this program. Now, today I'm going to show you two applications of our data-driven approach. First is the clinical dose selection for ALKS 2680 in NT one, NT two, and IH. Secondly, I'll introduce Project Saturn, our orexin portfolio expansion strategy, and show you how we are advancing the new orexin-2 receptor agonist based on data-rich translational models and integrated analysis. The biology here has a broad potential applicability, so having a comprehensive data-driven framework is essential for assessing and prioritizing these opportunities. So let's begin with dose selection in early development. Now, as you're aware, there are a number of highly potent orexin-2 receptor agonist currently in the development, where small differences in doses could really result into bigger differences into their clinical profile. How well a dose selection is done for these molecules is gonna be very critical and will really differentiate them from one another. So let me show you how robust our approach is. What you see here is a simple schematic depicting the process. Now moving from left to right, we determine the most appropriate experimental studies to generate relevant and informative data sets. Now, selection of conduct of these experiments are critical, but that's not where the proprietary insight lies. The insights come from organizing the data, and modeling and integrating them into a decision making frameworks. Now, this is where we have, in Alkermes, a great deal of experience, really translating from the animals to the clinical data sets, which have led to approved medicines. Now, let's apply this framework to initial clinical dose selection for ALKS 2680. Again, from moving left to right, we conducted series of preclinical experiments, asking and answering different questions related to safety, efficacy, PK, and pharmaceutical properties of ALKS 2680. In addition to doing the narcolepsy-specific assays, such as DTA mouse models, we also tested ALKS 2680 in modulating brain wave activity using quantitative EEG methods that are highly translatable to humans. Additional studies characterized the physicochemical and pharmacokinetic properties of ALKS 2680 in vivo. Now, taken together, these experiments generated a substantial amount of data. Now, this was a raw input for our integrated modeling to investigate exposure-response relationships and to inform parameters that are critical for achieving those efficacy and safety targets. The output of these models include, you know, an anticipated PK profile, which is concentration of ALKS 2680 in brain or plasma after oral administration over time, or exposure response profiles, which is an anticipated effect related to either safety or efficacy per unit of exposure in brain or plasma. Now, with that information, we selected range of doses calculated to achieve those target concentrations in brain or plasma in humans within our model parameters of safety and efficacy. The modeling we conducted for ALKS 2680 program informed us that the PK profile support once daily dosing in the target patient populations and also enabled our dose selection for our early clinical studies, which began with healthy volunteers and then into patients of NT1, NT2, and IH. Now, in case of 2680, our modeling turned out to be accurate. The doses we chose for phase 1b bracketed the expected efficacious dose range as we had predicted. The phase 1a and 1b program we conducted for ALKS 2680 tested our hypothesis and gave us the early evidence of safety, PK, and efficacy in patients. It also generated a significant amount of information to inform our dose selection for phase 2. Now, the important point to consider here that's shown in the left side of this slide is the phase 0 study. Now, before we even began our phase 1 program, we conducted phase 0 study, which was essentially a dry run for our phase 1b. The phase 0 study was designed to inform operational feasibility as well as the appropriate study design for phase 1b. We enrolled not only patients with narcolepsy in this trial, but also sleep-deprived healthy volunteers. This was an observational study, so there was no drug intervention. The phase 0 study informed us that the patients would offer more reliable data for estimating our phase 2 dose range. Whereas the sleep-deprived healthy volunteers, neither was able to replicate the sleepiness profiles we see in patients with narcolepsy, nor was able to capture that inter-patient variability in MWT. Now, looking down the left lanes on this slide, the single and multiple ascending dose study gave us the safety, tolerability, PK, and our first indication of CNS activity with qEEG. As we cleared the doses in MAD, we moved swiftly into our patient cohorts. The phase 1b cohorts in each of our target patient populations gave us this patient-specific data on safety, PK, and efficacy using MWT, as you've seen, which is the same endpoint in our current phase 2 as well as will be for our phase 3 trials. The four-way crossover design collected the information in a systematic way. And it was designed intentionally to better address the variability and establish a clear dose response. Collectively, the data from healthy volunteers and patients were integrated and analyzed to generate the population-based simulations designed to predict the response and its associated variability in a larger sample sizes. The output of all of this is estimation of therapeutic windows for a variety of safety and efficacy thresholds, and in each of that target populations of NT1, NT2, and IH. And this ultimately allowed us to make the data-driven decisions for our trial designs and what doses we want to take to phase 2 studies. Now, here's a visualization of what these models can yield. For competitive reasons, we are not showing the actual data, but you, you'll get a sense of the output. What you see here is an estimation of a probability of achieving a given target, and in this case, an efficacy target as a function of dose. The population-based analysis simulates a cohort of 200 to 500 patient profiles and estimated the probability of achieving a target profile, and an associated variability. That efficacy target is customizable. You could specify a target of, let's say, in a sleep latency in an MWT of 25 minutes, to be achieved in over 90%-95% of the patients. The dark blue line here denotes the probability or the average probability for the target population, and then the dotted line around it represents the distribution around that mean. In other words, the modeled variability across that 200 to 500 simulated patients. Now, you can see that as the dose goes up, you increase the probability but also decrease the variability achieving that efficacy target. Now, if you were to lower an efficacy target to, say, an MWT of only 20 minutes or greater, the curve will shift to the left, indicating that we can achieve a higher probability of achieving that target at even a lower doses. Now, a similar approach is then applied to targeted safety and tolerability profile. We set a target threshold for our safety profile and model the probability as a function of dose. The light blue line shown here is an average population probability, again, showing and the dotted line again showing that variability around that mean. So in contrast to the efficacy curve, where we are looking for doses where to achieve a high probability of achieving that efficacy target, in safety, in contrast you know, however, we are looking for doses with a low probability of exceeding the threshold. The result is the green shaded area, which represents range of doses, which at the left edge represents a profile which has a meaningful efficacy with a very low risk of exceeding that safety threshold. Whereas on the right edge, you see a profile that maximize that efficacy response at an acceptable safety or tolerability level. More importantly, this modeling is taking into account the expected variability around the means for both. Now, this robust data-driven approach provides a higher precision to our dose selection decisions. For 2680, such analysis informed our decision to take four, six, and eight milligrams into our phase 2 study in NT1 patient, which is Vibrance-1, and as well as 10, 14, and 18 milligram as doses, to our phase 2 study in NT2 patients, which is Vibrance-2. Now, when we complete the phase 2, we'll get another large increment of that data. We'll put that into the models, for our phase 3 dose selection. Now, with that as an introduction to some of our translational methodologies, let me move to where we are applying that. As you've heard this morning, the orexin mechanism may have utility in addressing symptom domains such as mood, cognition, fatigue in addition to the wakefulness. Now, this provides an opportunity to explore a broad range of neurology and psychiatry indications. Now, we can harness this in two ways. First is by leveraging the orexin mechanism on its own, which begins with narcolepsy, which is characterized by an absence or a dysfunction in orexin signaling, but it also includes a range of diseases where the orexin modulation by itself could be beneficial. The second way is to expand the spectrum of activity of orexin-2 receptor agonism by combining it with the established mechanisms. That results into a targeted polypharmacology approach. This is the same slide you saw earlier that Brian showed, you know, mapping this breadth of CNS activity driven by the orexin-2 receptor pathway. The orexin mechanism activates a neurocircuitry that's applicable beyond wakefulness in narcolepsy and IH to other symptomatic domains, such as mood, cognition, fatigue, as well as attention. The rat brain shares the same basic anatomy and neurocircuitry with humans, as shown here with some of the key brain regions that are known to be involved in pathophysiology of some of the symptom domains mentioned in my previous slide. The human circuitry activated by orexin-2 receptor agonist can be recapitulated in rat. Here we show a neuronal activation across the key brain regions measured by a transcription factor called c-Fos. The boxes in these regions represents or corresponds to degree of activation, driven by two different dose levels of one of our orexin-2 receptor agonists. Darker colors in these boxes represents greater activation. You can also see the regions, whereas shown in white, with no activation, such as locus coeruleus. Now, this also speaks to high selectivity of our molecules. Overall, what we saw is a highly significant dose-dependent activation across an array of these key brain regions. Now, let's take a deeper look into two of the most important brain regions, medial prefrontal cortex and nucleus accumbens. Both of them demonstrated a significant c-Fos activation with our orexin-2 receptor agonists. The medial prefrontal cortex is a key brain region that's associated with a executive functioning or higher level of decision making, complex cognition, attention, impulsivity, as well as a long-term memory. The nucleus accumbens is also an important region that's associated with motivation and reward processing. On the left-hand side, you see a bar graph with the increased neurotransmitter levels in these regions. Now, this data is shown as in the form of a stack plot that represents the relative proportional changes of these neurotransmitters within that region. What we saw is both in prefrontal cortex as well as nucleus accumbens, we saw significant changes in acetylcholine and histamine. Now, acetylcholine is known to be involved in many functions, including memory, motivation, sleep, and learning. Histamine is also known to be involved in regulating sleep-wake cycle, motivation, and as well as neuroinflammation. In addition, we saw a statistically significant change in serotonin in prefrontal cortex, which is also known to be involved in regulation of mood and sleep. Now, this circuitry, along with the observed neurotransmitter changes, provide us a roadmap for investigating these additional indications. There are a variety of indications across neurology, psychiatry, as well as select orphan and rare diseases with serious unmet need in one or more of the symptom domain, where this mechanism could have utility either by itself or using a targeted polypharmacology approach. At Alkermes, we are investigating several candidate molecules to pursue this broad opportunity. ALKS 2680 is the first molecule to emerge from this portfolio of orexin-2 receptor agonists, and it's focused on these core wakefulness indications of narcolepsy and IH. Its chemistry, PK, as well as pharmaceutical properties, is designed specifically for these indications. We recognize, however, that going beyond these indications of narcolepsy and IH, that other indications may require molecules with the different properties. So therefore, we have developed a nomination criteria, and it's well defined to suit these needs. The potency and selectivity of this can is foundational in this criteria, but other pharmaceutical properties come into play when mapped against the select therapeutic opportunities. Based on this nomination criteria, we expect to advance two additional candidates into clinical development next year. Parallel to advancing these candidates towards a clinic, we continue with our preclinical work, really evaluating additional therapeutic areas as well as symptom domains. In order to best vet and prioritize these opportunities, we are employing a data-driven, multifaceted approach that not only includes the preclinical studies, but also early clinical experience and experimental medicine studies to be done in targeted patient populations. The preclinical work is based on three pillars. First, qEEG. Now, qEEG, as we know, assesses brain wave activity. It allows us to profile the mechanistic as well as the molecular synergies and has a direct translatability to humans because we can measure the same properties in humans in a non-invasive manner in our early clinical studies. Second is microdialysis. Now, microdialysis is a technique to measure the increased neurotransmitter profiles and the impact of polypharmacology in a key brain regions in a conscious animal. And third is our select behavioral assays, which integrate this neurocircuitry and a neurotransmitter effects by measuring the symptomatic activity in a disease-relevant, translatable, animal models. Now, these three preclinical pillars is complemented by a fourth pillar, which is clinical studies conducted early during the development. These early translational studies are designed to leverage these preclinical findings and to enable our rapid insights into our target engagement, as well as the early efficacy indicators, in the clinic. Now, taken together, this is a very robust assessment program designed to identify and evaluate multiple therapeutic options, and it is well underway. Today, we're gonna show you more details on three areas: attention, impulsivity, and mood disorders. Now, these are just some of the; these are just the three of the many areas we are interested in investigating further. But, the data we'll show you today will give you a sense of the methodologies I've described here. So in order to just do that, I'm gonna invite next Dr. Julie Brooks, who is our Translational Pharmacology expert at Alkermes, and share with you some preclinical data. All right. Thank you, Bhaskar. Good morning. Hello. My name is Julie Brooks. I am a CNS director in the CNS Disorders Group in research here at Alkermes, and I am a neuroscientist by training. So, as you've heard throughout the day, the orexin-2 receptor pathway may have broad potential applicability beyond our core development program. To support our expansion strategy for Alkermes' orexin portfolio, we are utilizing emergent knowledge of the biological impact of our potent and selective orexin-2 receptor agonists to make data-driven decisions. So today, I'd like to walk you through two examples of how our preclinical team is utilizing multidimensional, translational preclinical models to identify and evaluate new potential clinical opportunities for orexin-2 receptor agonists. So, as Bhaskar mentioned, the preclinical team has implemented a three-pillar approach to data generation. The ability to make informed, data-driven decisions relies heavily on the strength of the assays used to generate that data. The strength of preclinical assays are derived from their translation to the clinic and their ability to reliably predict beneficial outcomes. As such, the preclinical team used these principles to guide the selection of which specific electrophysiological, neurochemical, and behavioral measurements would feed into our three-pillar strategy. S o let's take a look at the preclinical pharmacology strategy we use to assess opportunities in mood and stress disorders. We've already incorporated qEEG data into our development program, and this has been particularly useful in bridging preclinical to clinical assessments. So for today, I would like to focus on the other two, components of our strategy, specifically behavior and microdialysis-enabled assessment of neurotransmitters. We'll start with the selection and evaluation of the effects of an Alkermes orexin-2 receptor agonist using a gold standard rodent model of stress-induced disorders known as the chronic social defeat model. So we use the chronic social defeat model to induce robust, depressive-like phenotypes in preclinical species in order to test the therapeutic impact of an orexin-2 receptor agonist. Briefly, a test mouse is placed into the home cage of a much larger aggressor mouse. These mice are allowed to physically interact for approximately 10 minutes. During this time, the aggressor mouse often engages in a series of social confrontations with the test mouse because it views it as an intruder. Following this physical stress, the two mice are then separated by a barrier placed inside the cage and remain housed this way for 24 hours. This barrier contains small openings that allow the test mouse to continue to hear, see, and smell the aggressor mouse, contributing to additional substantial sensory stress. After this phase, the test mouse is then removed and placed into another cage with another aggressor mouse, and the process starts again. This is repeated consecutively for 10 days, and in response to this, a subgroup of mice will develop enduring physiological and behavioral phenotypes similar to depression. Social avoidance is an example of one of these behavioral phenotypes, which we can use the social preference test that's shown on the right to measure. After chronic social defeat, test mice are placed into the novel arena that contains an interaction zone in which a wire chamber is placed. The test mouse is given time to explore this arena under two different conditions: one, when the wire chamber is empty, and the other, when the wire chamber contains a new aggressor mouse. A social preference score is then calculated by dividing the time spent in the interaction zone when an aggressor mouse is present by the time spent in that same zone when the wire cage is empty. I'll show you what that looks like on the next slide. So mice are inherently social creatures, and they find social interaction very pleasurable. This is reflected in the control animal social preference test score that is graphed in black. These animals have not undergone chronic social defeat and thus spend more time in the interaction zone when there is another mouse present in the wire cage. For reference, any score below 100% or chance is considered to be social avoidance. Interestingly, the chronic social defeat model approximates individual variability in stress responsivity that's observed in humans. Specifically, exposure to chronic social defeat consistently leads to the development of one of two types of behavioral responses in the social preference test. One is referred to as a resilient behavioral response. This subgroup of resilient mice, represented on the graph in blue, maintains a high degree of social interaction when another mouse is present inside that wire cage, with a social preference score that's also comparable to control. On the other hand, a subgroup of mice who are more susceptible to the stress of the chronic social defeat paradigm, represented in red, actively avoid that social interaction zone when another mouse is present in the wire cage. This leads to a social preference score that is below 100%. Given the emergence of a depressive-like phenotype in this subgroup, we used the susceptible mice for additional testing. Those mice that displayed susceptible behavior were randomly assigned to one of three therapeutic interventions, and these include two FDA-approved treatments, ketamine and fluoxetine, as well as an Alkermes orexin-2 receptor agonist. Ketamine was dosed once on day one of the treatment period, where fluoxetine and orexin-2 receptor agonist were dosed once daily for fourteen days. At the end of the treatment period, mice were subjected to a second social preference test and were assessed for restoration of resilient-like behavior. As I mentioned, the ability of an assay to predict potential clinical efficacy is important for enabling data-driven decision making. The social preference test exemplifies this by demonstrating sensitivity to two FDA-approved agents with different mechanisms of action. Similar to the previous slide, you see the social preference scores for susceptible mice are less than 100% at baseline, and this is not impacted by vehicle treatment. However, administration of fluoxetine, an FDA-approved selective serotonin reuptake inhibitor and a standard control for this preclinical task, showed an antidepressant-like effect in susceptible mice, as indicated by the significant increase in social preference score after dosing, which is shown in blue. Another FDA-approved treatment, ketamine, also showed an improvement in social preference scores in the susceptible mice. Furthermore, this assay approximates clinical dosing regimens, with fluoxetine requiring chronic dosing, in this case 14 days, compared to a single dose of ketamine, which is associated with a more rapid onset of effect. What does an orexin-2 receptor agonist do to the social preference scores of susceptible mice? Alkermes' potent orexin-2 receptor agonist demonstrated dose-dependent antidepressant-like effects in susceptible mice similar to fluoxetine and ketamine. Now, while our initial studies used a fourteen-day dosing period, additional studies are ongoing to assess whether the orexin mechanism may offer a more rapid onset of effect. In addition, given these encouraging behavioral results, we have also begun to evaluate the biological processes that may contribute to the effects observed. Of particular interest is understanding changes in neurotransmitters, including those associated with mood and stress disorders, and we'll take a look at that next. Microdialysis is a technique that is used to collect samples of extracellular fluid from the brain, which can then be quantified for neurotransmitter content. To do this, a microdialysis probe is implanted into a brain region of interest and perfused with artificial cerebrospinal fluid. The tip of the probe is semipermeable. This permits neurotransmitters to move across the membrane along their concentration gradient. The perfusion solution is then collected and analyzed for neurotransmitter content. So using this technique, we measure changes in neurotransmission induced by treatment administration. While this technique allows us to simultaneously evaluate several neurotransmitters in a given experiment, today's data will focus on serotonin, as deficits in serotonin neurotransmission are believed to contribute to symptoms of depression, and many FDA-approved treatments for mood disorders restore these deficits. Finally, we chose the prefrontal cortex as our brain region of interest, given the importance of this cortical region in both mood regulation and goal-directed behavior. Allow me first to orient you to this graph, as you will see several like it throughout the presentation. This is a time course graph showing% change from baseline levels of preclinical, or sorry, prefrontal cortical serotonin before and after treatment. Each data point represents a measurement obtained from a thirty-minute sample collection. As expected, based on the mechanism, administration of a selective serotonin reuptake inhibitor significantly elevated prefrontal cortical serotonin, and that's demonstrated in purple. We also observed a modest but not significant increase in this experiment in prefrontal cortical serotonin in response to an Alkermes orexin-2 receptor agonist, which is illustrated in blue. Interesting, when the Alkermes orexin-2 receptor agonist was co-administered with the same dose of SSRI, we observed further enhancement of the SSRI-induced increase in prefrontal cortical serotonin, which is shown in green. These initial data suggest that activation of orexin-2 receptors may engage other aspects of mood-related neurocircuitry beyond serotonin transporter inhibition, which may provide opportunity for further enhancement of orexin, SSRI activity with this polypharmacology approach. So to summarize this section of preclinical data, the antidepressive-like effects observed in susceptible mice following the chronic social defeat model suggest there may be an opportunity for an orexin-2 receptor agonist as a novel approach in mood disorders. In addition, early evidence that co-administration of an orexin-2 receptor agonist with an SSRI in rats enhance SSRI-induced serotonin neurotransmission within the prefrontal cortex indicates potential for additional benefit through this polypharmacology approach. It is worth noting, however, that in our preclinical assessments, the therapeutic profile of a combination approach with an Alkermes orexin-2 receptor agonist varied based on the choice of mechanistic partner, with some combinations demonstrating additive benefit, some demonstrating interference with the established agent, and some having a neutral effect, neither enhancing nor interfering with the established pharmacology. So now I'd like to transition to our preclinical pharmacology strategy to assess opportunities in attention and impulsivity disorders, which are currently treated with stimulant and non-stimulant agents. Again, I will focus on behavior and microdialysis components of our strategy, starting with the selection and evaluation of the effects of Alkermes orexin-2 receptor agonist, using a gold standard Five-Choice Serial Reaction Time Task to assess attention and behavioral impulsivity in preclinical species. The Five-Choice Serial Reaction Time Task is a data-rich behavioral assay with high clinical translation. In fact, this task was back-translated from the human continuous performance task, which is still used in clinical settings. Given this, it's not surprising that many FDA-approved treatments for attention deficits and impulsivity show comparable improvements on rodent behavior in this task. Both stimulant and non-stimulant agents have been tested with this assay, with each showing improvement on different aspects of behavior measured with this task. In the five-choice tests, shown on the left-hand side of the screen, animals are trained to respond to a light stimulus with a nose poke in order to receive a food reward. If an animal makes a nose poke response prior to the light stimulus being presented, this is labeled as a premature response and is used as a measure of behavioral impulsivity, and that's illustrated on the top right-hand corner of the graphic. Now, this might seem like a pretty simple task. However, there are five different locations where a light stimulus could be presented, and the rat must pay attention to the location of the light and nose poke to the same location in order to get rewarded. This is referred to as a correct response, and that's illustrated on the lower left-hand corner. Failure to do so, either by not responding, which is labeled an omission and shown in the middle, or by inappropriately nose poking to a different location, labeled an incorrect response, which is shown on the lower right, results in a timeout for the animal and no food reward. Counting the total number of trials an animal completes based on the number of correct, omitted, and incorrect responses is used as a measure of attentional performance and task engagement. Changes in the Five-Choice Serial Reaction Time Task result in different behavioral responses across subgroups of rats. For instance, shortening the intertrial time, this is the period of time between when one trial ends and the next one begins, leads to more trials being presented at a much faster rate, which challenges the attentional capacity of the animal. This results in a decrease in the total number of trials completed in a subgroup of rats that we call low performers. As you can see in the bar graph on the left, the high performers, which are shown in black, are not impacted by this challenge and are able to complete almost all of the 120 trials possible within the task. However, the low performers, which are shown in gray, find this to be particularly challenging and complete less than half of the total trials possible. So let's see what happened when we treated those same low performers with an Alkermes orexin-2 receptor agonist. Here, we are only looking at the low performers, again, still graphed in gray, who completed a limited number of task trials when given vehicle. We can compare that to the same low performers when treated with an Alkermes orexin-2 receptor agonist graphed in blue. Now, these low performers completed a significantly greater number of trials, even under this challenging task condition. So to provide context, let's see the impact of an FDA-approved treatment on this test. We are conducting this test with several different agents, but for today's data, we will be focusing on a specific ADHD non-stimulant treatment. We found that administration of an ADHD non-stimulant treatment did not improve total trials completed by low performer rats, and that's illustrated in teal. Importantly, we did observe an increase in total trials completed when Alkermes orexin-2 receptor agonist was co-administered with the same dose of that ADHD non-stimulant treatment, suggesting that an orexin-2 receptor agonist may be complementary to the clinical activity of this non-stimulant agent. A key feature of ADHD non-stimulant treatment is their efficacy in controlling impulsive behaviors. So are we able to measure this aspect of this agent? And the answer is luckily, yes. As I mentioned, we can assess changes in behavioral impulsivity by measuring the number of times a rodent makes a nose poke response prior to the light stimulus being presented. And again, that's illustrated up at the right-hand corner of the figure. Lengthening the inter-trial time delays the animal's progress to the next trial and slows their ability to collect their next food reward. This leads to an increase in impulsivity in a subgroup of rats we will refer to as high impulsive, which are represented in gray. Compared to low impulsive rats, again, graphed in black, high impulsive rats make an exceptionally high number of premature responses under this longer inter-trial time condition. So how do these animals perform under following treatment with an Alkermes orexin-2 receptor agonist? When given vehicle, again, shown in gray, high impulsive rats continue to commit high number of premature responses. However, when the same high impulsive rats are treated with an Alkermes potent orexin-2 receptor agonist, again, graphed in blue, there was a significant decrease in impulsive premature responses. Again, for context, let's see how an FDA-approved ADHD non-stimulant impacts this task. Treatment with an ADHD non-stimulant, again, shown in light teal, significantly lowered the number of impulsive premature responses, and the magnitude of this effect is comparable to what we observed following an orexin-2 receptor agonist treatment. In addition, co-administration of Alkermes orexin-2 receptor agonist with the ADHD non-stimulant treatment did not interfere with this effect. Statistically speaking, the three interventional arms are the same. So let's take a step back and look in totality of what this data is telling us. First, the Alkermes orexin-2 receptor agonist improved attentional measures in this model, both alone and when co-administered with an ADHD non-stimulant treatment. Second, the Alkermes orexin-2 receptor agonist demonstrated benefit on impulsivity alone, and when co-administered, did not interfere with the effect of the ADHD non-stimulant, suggesting the potential to maintain the clinical profile of this agent while broadening its beneficial impact on attention in a complementary way. Once again, we turned to microdialysis to deepen our understanding of these observations. The data I'm sharing today focuses on changes in prefrontal cortical acetylcholine induced by treatment administration. We chose acetylcholine because this neurotransmitter within the prefrontal cortex plays a key role in information processing, attention, and contributes to general arousal. Furthermore, enhancing prefrontal cortical neurotransmission of acetylcholine has been shown to contribute to effective attentional performance. We found that acute oral administration of an Alkermes orexin-2 receptor agonist significantly increased prefrontal cortical acetylcholine in rats, and that's graphed in blue. A similar but lower magnitude overall response was observed following acute oral administration of the same ADHD non-stimulant treatment that we used in the five-choice serial reaction time task study. To our knowledge, this effect on prefrontal cortical acetylcholine has not been previously documented for this non-stimulant treatment. When we co-administered the orexin-2 receptor agonist and the ADHD non-stimulant treatment, we observed a prolonged elevation in prefrontal cortical acetylcholine, which significantly separated from the effects of the orexin-2 receptor agonist alone at the end of the experiment, graphed in green. So in summary, we were able to identify validated preclinical models of attention and impulsivity that provide translational value to our data-driven decision-making process. Improvements in measures of attention and task engagement, coupled with decreased behavioral impulsivity, as assessed using the five-choice serial reaction time task, suggests an opportunity for an orexin-2 receptor agonist as a novel therapeutic approach, whether administered alone or co-administered with, to expand the therapeutic dimensionality of an ADHD non-stimulant treatment. In addition, early evidence of prolonged prefrontal cortical acetylcholine following co-administration of an Alkermes orexin-2 receptor agonist and an FDA-approved ADHD non-stimulant treatment suggests an opportunity for additional additive benefit. So overall, the selection of preclinical data that I shared today demonstrated significant effects of an orexin-2 receptor agonist on prefrontal cortical neurotransmission, cortical arousal, and symptom-relevant behavioral assays with strong predictive validity. These data indicate that orexin pharmacology, coupled with credentialed existing pharmacology, may open new opportunities to address unmet need in a broad range of neuropsychiatric disorders. Most importantly, though, the strength, consistency, and reliability of preclinical assessments used to generate these data enable us to make informed decisions regarding clinical candidates and indications of interest. So with that, I t hank you for your attention, and I will turn it over to Rich Pops, our CEO, for closing remarks. Julie, thank you. That was your dose of science for the day. I hope you all enjoyed that. I wanna thank Julie. I wanna thank our clinician researchers. I wanna thank all of the presenters for all the work you guys put into this today, and thank those of you in the room for coming. You've had a lot, so I'm gonna be quite brief and just summarize a couple key points here. First of all, with respect to ALKS 2680 in narcolepsy and IH, what you've seen is that from the very beginning of this program, we've brought the considerable amount of experience we have at Alkermes to bear, not just in the molecular design and the pharmaceutical properties, but also the competitive commercial aspects of the drug we've built in from the outset.... The program now is and always has been rooted in data. In not just the generation of data, but the statistical analysis and the analytical methodologies that goes into making decisions based on those data. NT one, NT two, IH, these patients share common clinical features, common symptoms, but our thesis from the beginning was that we were gonna need a range of well-tolerated doses in order to address variability. Variability of the disease, as well as variability in each individual patient's potential treatment outcomes, their desires in their lives. The phase II program is now well underway. In NT one, NT two, we're enrolling studies, multiple doses in multi-center studies, and those are tracking beautifully. We'll have data in the second half of next year. You also heard today that we're, we made the decision that you knew we were, we were noodling on about IH. And the reason we made that decision was based on feedback we got from patients and clinicians in the wake of the phase 1b data. And what we heard clearly was there's a huge unmet need for new medications in this patient population. You've heard a bit of that today. And also, there are a lot of patients who are suffering, and so it just stand to reason, given the, the fluidity of the diagnosis between NT one, NT two, and IH, why, why arbitrarily stop? So we're gonna move in that area as well, and it's, it's a big opportunity. So what's left to be done? What's left to be done is the phase 1 data were quite clear. Now we need to augment that data set with daily dosing over a multi-week period in the outpatient setting, and that's what phase II is all about. The phase II is designed anticipating phase III. So all the work we're doing, the infrastructure we're building clinically now, is anticipating a successful result in phase II. If we get that, we'll be able to light off phase III and potential registrational studies very, very quickly, and that's exciting. Sites, investigators, study design, that's all being integrated into the phase II program right now. So when we think about ALKS two thousand six hundred and eighty in narcolepsy and IH, it's quite exciting because it's, there's a potential to create a real meaningful increment in the standard of care for patients. That's a huge opportunity for patients, for the clinical community, and obviously for Alkermes and its shareholders as well. So we love where we are in this position right now. We like where we are. We're moving very quickly. We've always believed in the biology. Our goal has been to make the best medicine for patients. So if the story of orexin begins with narcolepsy and IH, none of us think it's gonna end there, and you got a sense of that from Julie. In fact, in the fullness of time, interrogating the circuitry in the brain may have profound consequences in broader indications, including opportunities in neurology, in psychiatry, and in orphan and rare diseases. Our Project Saturn, that you just got a glimpse of, is investigating orexin two receptor agonist in highly translatable models, and we're doing that in two ways: monotherapy, as well as combining it with credentialed mechanisms that we know have activity in clinical settings for patients, creating new dimensionality, potentially for new medicines that can really help patients. This is an area that we love to play in. This is very Alkermes in the sense of taking credentialed biology and engineering new, highly engineered molecules, conferring new clinical benefits for patients. Molecular design, driving new effects for patients in credentialed settings of biology. That's where our sweet spot has been historically. It's where we've competed, and it's where we've succeeded in the past. Foundational to these expanded opportunities is the medicinal chemistry, this portfolio of additional orexin agonist molecules. You've learned that space is difficult from a medicinal chemistry perspective. We have standing there, and we've nominated two additional candidates that we're moving into the clinic next year. So that's where we stand, right? We gave you a lot today, but I hope you can see that the program is rich, it's scientifically rich. It's just at its beginning stages in many ways. The portfolio is expanding, and we're moving as fast as we can to the first real proof point, which will be, I think, the completion of the phase II studies next year. So we've had a hell of a 12 months behind us, and I think the next 12 months are gonna be every bit as exciting as the ones we've just experienced. So with that, I think we'll move to the Q&A and let you guys ask some questions for us. All right. Let me ask Craig, Bhaskar, and Julie Himes to please join Rich at the front. Our other presenters and our clinicians here will be here, available for questions as well, but for space, we'll run it like this. Hi there, Joseph Thome from TD Cowen. Thank you for the presentation. I actually have a question on the last portion of the presentation in terms of the additive benefit in ADHD. I guess, how are you thinking about the actual need for that non-stimulant option, given that it didn't look like the non-stimulant actually provided additional benefit in the rodent models above what the orexin was doing? It kind of seemed like the orexin was doing all the heavy lifting. And then second question on some of these combinations, how easy is it to model DDIs and AE's in preclinical models with the orexin? Obviously, you're seeing some added benefit in depression, but, how much can you de-risk the tolerability profile of this? Yeah. So, I'll take two, you know, to both questions. First is around the, you know, what's the need of orexin for, in when it's doing all the heavy work? I think our program was designed to take a look at the impulsivity as well as the attentional benefits. And, our hypothesis was that the-- we're not gonna have like a. You know, I think the non-stimulant is gonna give you that- ... impulsivity response that you need, and the orexin will add it into the or task, you know, the attentional dimension to that, to that therapeutic. So that's kind of our current hypothesis. As we get more data and you know, generate more data, we'll definitely be able to give more information on that one. When it comes to DDI, you know, to your other question, our nomination criteria included all of those considerations when it comes to metabolic profile and then some of you saw in Brian's presentation the PK profile. All those factors still apply to our two new molecules. We looked at the mechanistic partners, their metabolic profile, the DDI, and it's how we selected, and those two candidates we've selected have a very low likelihood of any DDI potential. So we are very confident in our profiles, that we are bringing these two molecules that really gonna has the potential to change the treatment landscape. Maybe just to add in, on what Bhaskar said, with the first half of your question. You know, there's a lot more work which is ongoing in parallel. We obviously are gonna be looking at different doses and seeing how those react, too. And so I think, collectively, you know, we'll be looking at all the assays that you saw presented today and within the context also of different doses as well as we move forward and make decisions. Hi, David Amsellem from Piper Sandler. I wanted to focus on the preclinical data in models of depression, mood disorders. It seems like, and I hope I'm reading this correctly, that there is potential single agent activity, but also activity as adjunctive therapy, adjunctive treatment to an SSRI. So that sort of raises an interesting question, which is: How do you approach a development program in major depressive disorder or potentially, you know, other subgroups of depressed patients, whether it's treatment-resistant depression, whether it's bipolar depression? And so there's a lot of white space here, but, and I know these are preclinical models, but help us better understand at least in a broad sense, how you're thinking about it, given what you're learning so far. I'll let you guys start, and then I'll give my point of view. I think I go back... I mean, to your question, I go back to the framework I presented. I think the way we developed is we are collecting a lot of preclinical information. We are understanding the efficacy, the impact and benefits on this different symptom domain. We're also looking at, the fourth dimension, which is our early clinical studies, where those will be done in a target patient population looking for early indicators, and how do we profile them? How do you-- You know, it's, it's really, it's included into our... So, how we look at in terms of the single agent, and then those studies will include single agent as well as the combining different mechanism, testing those aspects, and we'll obviously make that evaluation based on that data. Maybe just to add into what Bhaskar's said, there's obviously a lot of heterogeneity in MDD population- Yeah ... as we've all learned over the last number of years, and so, you know, I think as we move forward, we'll be looking at specific subpopulations as well, and there may be certain subpopulations within the, sort of MDD that are better suited to an orexin-2 mechanism. In addition, as you heard us present, you know, we're moving two orexin compounds forward into the clinic next year. The profiles of those agents and either in combination or as single agents, will also. We'll learn more as we move forward. And so I think you'll hear more from us as we sort of refine and collect more information on doses and more specifics on the agents as to which populations or subpopulations and you know in indications like MDD are going to be important for us. See, my view is that CNS, particularly psychiatry, has been crying for the specificity that we see in other symptom domains or other therapeutic areas. So MDD is a completely non-descriptive clinical diagnosis. So you can contrast the specificity of the circuitry we're interrogating with an orexin-2 receptor agonist, the projections in the brain, the attentional centers, and we have so much precision about what the likely pharmacological impact of agonism is. To map then onto a completely vague clinical diagnosis doesn't make any sense to us. So I think what we've been looking for is instead of the classical demarcations between monotherapy and MDD, adjunctive therapy and MDD, TRD, are there more specific characterizations of the phenotype that you can map the circuitry onto? I think that we have some thoughts on that, and then we'll keep that under wraps for a while, but I think it's really exciting. Okay, I have two from our online viewers. First, a quick one: Are the OX2 agonists you are using in the preclinical models ALKS 2680, or are they one of your next-generation molecules? Bhaskar, if you want to- Yeah, sure. Yeah, the data you saw today is one of our two molecules that we are advancing into the clinic. And then here's one on 2680: How does the current safety data that you have give you confidence for longer-term dosing, especially at the higher doses, in the NT2 trial? Sure, I can start with that. So again, as we've advanced through our phase 1b program, where we've collected data across NT1, NT2, IH, again, still relatively small numbers, but we're very excited and confident moving into phase II. These will be larger phase II style studies, looking at those different dose levels, but also better understanding the durability of response and the profile of safety over long-term daily dosing. So we're very excited about that, particularly also the opportunity to allow patients with their- ... physicians with the investigators to dose adjust. I think that will also give us a lot of information. Yeah, maybe just to add to what Julie said, you know, I think the profile we've seen thus far, the adverse events have been predominantly mild. We've seen, you know, a few moderate adverse events, and these have all been transient in nature. So, you know, we've got confidence in the safety profile that's emerged thus far. Obviously, chronic dosing, we'll learn more in the phase 2 program. But I think also when you contrast that with the available therapies at the moment and the safety profiles and what have you, you know, we feel confident in the profile that we have for 2680. Thanks so much. This is Chi again for Jason Gerberry at BofA. I'm curious. I have a couple of questions on IH. I think if I heard you guys said correctly, you plan to start the IH phase 2 study only after you have completed the phase 2 dose in narcolepsy. Okay. No, no, not the case. Okay. Sorry about that. So curious, what dose are you-- what dose range do you plan to move with the IH? Would that be similar to phase 2 for the NT2 or different than NT2? Along the same line, looking at the IH data in phase I, looked like the placebo effect is pretty variable, similar to the NT two population, and from what I understand, in the phase II design for NT two, you plan to restrict the baseline and MWT to a certain level, and I'm curious if you're doing similar strategies for the IH study as well? I'll take that. I'll start with those two, and the first question is around the dose selection for IH. So we're currently in the process of doing that. Obviously, you saw our approach of dose selection. It involves a lot of analysis, integrating different factors. So we haven't really made the decision on the doses for IH yet, but traditionally in this space, you know, same doses have generally been effective. They are effective in NT2, similar to what we saw in a phase 1b. So we'll update you with that in a year, you know, next year when we actually have the study design completed. The second aspect around the variability. The variability, obviously, we saw higher variability in our phase 1b. Didn't stop us to actually see a statistically significant effect. So you saw a clear dose response into our dose selection. We actually took that into account in terms of what the sleep limit we will set for the MWT. So all of that aspects involved within our consideration of modeling and selection of doses. And then maybe just to add in on- Yeah. your question on the trial design. We're actually in the process at the moment of refining the trial design. You know, obviously, once we've got a better idea, we're also going to ensure that it meets sort of regulatory requirements and ensure that we have those discussions as well. So, that's... We'll be able to give you sort of a better idea of what that looks like, probably early next year. Mm-hmm. Because people may not have been able to hear my head nod, we won't wait to start that IH study for the completion of the narcolepsy. It'll start as soon as it's ready to go. Okay, thanks so much. Thank you. Chris Shibutani from Goldman Sachs. A question on the regulatory dynamic here. Just remind us what your expectation is for, the sort of duration of exposure and the number of patients that ultimately will be needed for a filing? I think the FDA has thought about sometimes treatments for a particular disease category, but certainly we're seeing more emphasis on treatments based upon mechanism, and obviously we haven't had the orexins yet available there. So I'm just curious in that regard. And then for the KOLs who are part of the panel, how do you think about the availability of multiple dose ranges ultimately? Obviously, we're kind of doing clinical work here, exploring different dose ranges to see the optimal profile, but practically speaking, when you're managing patients who seem to be inherently heterogeneous, what is the value? What would be sort of the sweet spot for you in terms of the number of available doses that you think ultimately would be appropriate when you're taking this into the real world? So maybe on your regulatory question, you know, at this point in time, our belief is it's the most important factor is for us to generate our phase II data, and the strength of the phase II data will inform what our phase III program will look like. So that's our sort of primary focus at this point in time. You know, obviously, we also do have sort of an idea of what trials are being conducted in the phase III setting at this point in time, and we know what those sort of sizes look like. But I think a large part of this is gonna be the strength of our phase II data, and having those interactions at the end of phase II that will decide what the phase III program looks like. Take a crack at that, Justin? Sure. In terms, from a clinical perspective, in terms of having a range of dosing, the broader the range, I think, the better. It's very common to see patients, I mean, some people respond exquisitely to a very small amount, less than sort of the starting dose, even, of a given medication, but oftentimes, people need more than what's indicated or approved, and those people can sometimes be a little bit tricky, so having a wide dose range where you know a compound is safe is very helpful from a clinical standpoint. Marc Goodman at Leerink. Can you talk about the two, second-gen products or whatever you wanna call them, the backup molecules, how the characteristics are different from 2680? So maybe I'll start. You know, all of our compounds are macrocycles, but have differing PK and PD profiles, and based on the PK and PD characteristics, we'll be able to fine-tune which orexin agonists are best suited to which indications and which part of the compounds. ... So we'll be able to inform, as we get more information, we'll be able to give you more of an update, as we progress. Which, Mark, is a long way of saying, "No, we're not gonna tell you too much about them in specificity," but they're different, and they share common characteristics of potency and selectivity. I mean, they all need to be potent selective to make it through nomination. Okay. I have another one from online. This one's from Uy Ear, Mizuho. Can you elaborate on the unmet need in cognition and your level of excitement about recent orexin data showing improvement in cognition on multiple domains? And how important is this to demonstrate improvement across multiple domains? So I might ask Dr. Maski maybe to chime in on that, and then if the Alkermes team has something to add. Yeah. I mean, I think, from experience with the practice parameters, that was a very organic process where we were looking at outcomes that were relevant to patients and soliciting feedback from patient groups, to identify that. And so sleepiness and cataplexy, of course, were important, but cognition and fatigue ended up being, like, very high in what patients were looking for, for optimal, probable quality of wakefulness, really. And so I think that those outcomes were not traditionally assessed in older generation studies, and so now we're starting to see them included. And so the fact that they are showing robust improvement with orexin agonist, I think is really exciting, and it's really important to include in future clinical trials as well as fatigue. Just to add to that, and thank you. I think it's obviously clear from what Charlie's presented, the importance of these other factors, the patient outcomes beyond sleepiness, beyond, you know, the difficulty in maintaining wakefulness, so specifically, we have included in our phase II program standardized means to collect information about cognition so that we can fold that into our phase III and really expand in our understanding of the profile of ALKS 2680. Okay, got another one online. Will NT two read out earlier than NT one, given there is more competition for enrollment in the NT one space? We're in the process now of activating our sites and in the early stages of screening and enrollment. Very brisk, very exciting, but I think it's a little too early to predict exactly when those two trials will fall in relative to each other. We are anticipating data readout, as we've said, in the second half of next year. Great. Anyone else in the room? One here. Jamie. Hi, Mark Hitrik from Stifel. Just had two questions. One, if you guys could provide a little bit more color around the visual disturbances and kind of how those patients presented and, you know, ultimately how it resolved. And then beyond the ophthalmological assessments, would you expect to run any additional studies, like a driving safety study, that would satisfy the needs of the FDA? And then just the second question was around the dosing. We noticed that Takeda was splitting the dose and doing it twice daily, and then, your molecule is once dosed once daily, and, you know, why do you think that is? If you could give any, like, insights there. And just for context, we noticed that the twice-daily dose performed better than the once-daily dose for Takeda. Thank you. I can start with the visual, and then. I can- - you'll pick up with the- Dosing. Okay, great. So as you have mentioned, we did see several events of visual effects in the patient cohorts, none in the NT1 cohort, but at the higher doses in IH, we had one subject who had a visual effect, and in the NT2 cohort, one subject who had... They were both mild, incredibly transient, did not require any treatment or for resolution. So clearly, we're watching this, and we've incorporated into our phase II studies baseline assessments in order to better capture any types of changes we may see or may not see. So that's our plan for addressing this. Yeah, from dosing perspective, I'll go back to, I think, some of the concept that Brian actually showed, you know, shared with you earlier. We are really very confident in how we selected, how we designed the PK of that and what we understand from its you know, the effective concentrations. That really translated into the efficacy data now we're seeing with the phase 1b, where a single dose given in the morning was able to maintain the wakefulness during you know, really provided during the daytime period. And really, you know, talking to the clinicians as well as even patients at some of you know, the sleep conferences, they really felt that there was no need for a second dose, and that really what we see as a differentiating factor. I think it's rooted into its PK/PD differentiations. Just one more click on that, just because- Yep. That PK profile, that waveform is so essential in this particular category. If it's too long, you might keep people up all night. If it's too short, you'll have to dose it repeatedly. So finding that sweet spot, and it's not just measured by the classic t1/2, which is the area under the curve from zero to infinity, it's above that threshold of concentration that drives wakefulness. So we modeled it, and it turned out to be accurate the way we modeled it, and that was then confirmed in the clinic so far. But I think that's a huge part of the differentiating feature of this particular program. All right. I have one more online, and then I think we're gonna wrap up pretty soon. So if there's any final ones in the room, the next is your chance. How important do you think linear PK is? Is your PK linear? There are other agents in the space that are saying that their PK is particularly unique because of that feature. I'll take that. The linear PK is obviously a desirable trait, and we do have a linear PK when it comes to overall exposure. We shared some of the data in our World Sleep meeting last year, where we showed those proportional increases in our total exposure. However, the design of this molecule is such that we actually have a less than proportional increase in the peak concentration, which actually help us with generating a more safety margins when it comes to AEs, without really compromising on the duration of efficacy during the day. So, it's how we thought through, how we designed it, and it's really and I'm very glad to see it materialize in the clinic, and it's really showing that clinical efficacy. Okay. I think that's a wrap then. Thanks so much for joining us, everyone, both on the webcast and in the room, and we'll look forward to updating you on our progress. Don't hesitate to reach out to us with follow-up questions. Thank you.