Good morning, and welcome to the Axsome Therapeutics Conference Call. Currently, all participants are on a listen-only mode. Later, there will be a question-and-answer session. As a reminder, today's conference is being recorded. I would now like to turn the conference over to Darren Opland, Director of Corporate Communications at Axsome Therapeutics. Thank you. Please go ahead. Good morning, and thank you all for joining us for Today's Solriamfetol Investor Event Conference Call. During today's call, we will be making certain forward-looking statements. These statements may include statements regarding, among other things, the efficacy, safety, and intended utilization of our investigational agents, our clinical and non-clinical plans, our plans to present or report additional data, the anticipated conduct and the source of future clinical trials, regulatory plans, future research and development plans, our commercial plans regarding Sunosi, Auvelity, and our pipeline products, revenue projections, and possible intended use of cash and investments. These forward-looking statements are based on current information, assumptions, and expectations that are subject to change and involve risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements. These and other risks are described in our periodic filings made with the SEC, the Securities and Exchange Commission, including our quarterly and annual reports. You are cautioned not to place undue reliance on these forward-looking statements, which are only made as of today's date, and the Company disclaims any obligation to update such statements. Joining me on the call today are Dr. Herriot Tabuteau, Chief Executive Officer, Mark Jacobson, Chief Operating Officer, and our distinguished guests, who will be introduced shortly by Mark. We will open the line for Q&A twice during the event, once in the middle of the event and then after the last guest speaker. Questions will be taken in the order they are received. And with that, I will turn the call over to Mark. Thank you, Darren. Good morning, everyone, and welcome to the Solriamfetol Investor Day event. We are honored to be joined today by five experts, each recognized as leaders in their field, who will discuss the background and treatment landscapes for solriamfetol's target indication, including a brief update on Axsome's clinical development plans. Joining us today are Doctors Craig Chepke, Andrew Cutler, Susan McElroy, Richard Bogan, and Charles Czeisler. Dr. Craig Chepke is the Medical Director of Excel Psychiatric Associates, Adjunct Associate Professor of Psychiatry for Atrium Health. Dr. Chepke will provide background on TAAR1 and an overview of major depressive disorder. Dr. Andrew Cutler is a Clinical Associate Professor of Psychiatry, SUNY Upstate Medical University, here today to discuss attention deficit hyperactivity disorder. Dr. Susan McElroy is Chief Research Officer and Director of Psychopharmacology Research at the Lindner Center of HOPE at the University of Cincinnati, and is joining us today to provide an overview of binge eating disorder. Dr. Bogan is Principal of Bogan Sleep Consultants, Associate Clinical Professor at the University of South Carolina School of Medicine, and Associate Clinical Professor at Medical University of South Carolina. Dr. Bogan will provide an overview of solriamfetol studies around cognition. Dr. Charles Czeisler is the Baldino Professor of Sleep Medicine, the Director of the Division of Sleep Medicine at Harvard Medical School, and Chief of the Division of Sleep Medicine in the Department of Medicine at Brigham and Women's Hospital. He's joining us today to discuss shift work disorder. Here is a look at today's agenda. Herriot will briefly provide an overview and update for our solriamfetol development pipeline before turning over to our guest speakers. First, Dr. Chepke will discuss the TAAR1 and its relevance to clinical indications, including MDD. Then Dr. Cutler will discuss ADHD and present recent clinical data for solriamfetol in this indication. Following their sections, we will have a Q&A session for Doctors Chepke and Cutler related to these topics covered in the presentations before proceeding with the rest of the event. The second portion of the event will start with Dr. McElroy speaking on binge eating disorder and the scientific rationale for solriamfetol in this indication. Dr. Bogan will then discuss recent clinical data on solriamfetol's effect on cognition. Finally, Dr. Czeisler will present on shift work disorder and the rationale for solriamfetol in this indication. Following their sections, there will be a final Q&A section for Doctors McElroy, Bogan, and related to the topics covered in their presentations. By the end of today's program, I hope you share our excitement for the potential of solriamfetol. I will now turn it over to Herriot to provide an overview of solriamfetol. Thank you, Mark. This truly has been an exciting year for Axsome, and I'm very proud of our team and all the hard work that has allowed us to grow into a fully integrated commercial-stage biopharma with an industry-leading CNS pipeline. Axsome has already two marketed products to complement a broad pipeline with five differentiated late-stage product candidates. These developmental drug products are now being advanced in nine target indications, which combined have the potential to treat upwards of 183 million patients in the U.S. Today, however, we will focus on just one of these molecules, solriamfetol, which we believe has blockbuster potential. Solriamfetol has unique pharmacology. It was initially developed based on its ability to inhibit the dopamine and norepinephrine transporter. ... Further research has revealed that it also has activity at the trace amine-associated receptor 1, or TAAR1, and the serotonin 1A receptor. Individually, these mechanisms of action have been associated with several effects in preclinical as well as clinical models, including weight-promoting effects, procognitive effects, antidepressant-like effects, and effects on weight and appetite. Solriamfetol's unique pharmacology therefore lends itself to several potential applications. In order to unlock the clinical and commercial potential of solriamfetol, we have taken the following approach. Careful elucidation of solriamfetol's pharmacology has allowed us to determine correlations between its mechanisms of action and the mechanisms of disease for potential target indications. We then generated clinical proof of concept data through the conduct of pilot clinical studies or the use of existing clinical data. The goal of this approach was to allow us to select new indications with the strongest scientific rationale, the highest probabilities of success, and the highest potential clinical impact based on the evidence. Utilizing this approach, we have previously announced our intention to develop solriamfetol for ADHD, binge eating disorder, and excessive sleepiness associated with shift work disorder. Today, we are announcing for the first time our intention to develop solriamfetol for another new indication, namely for the treatment of major depressive disorder. If we are successful, solriamfetol would represent the first TAAR1 agonist approved for the treatment of MDD. We intend to move expeditiously to develop these new indications. With that in mind, we look forward to the following near-term clinical milestones for solriamfetol. For MDD, we intend to initiate a phase III trial in this indication in the first quarter of 2024. Likewise, we are on track to initiate phase III trials in binge eating disorder and excessive sleepiness associated with shift work disorder, also in the first quarter of 2024. Our focused phase III trial of solriamfetol in ADHD is progressing well, and we remain on track for top-line results from the study in the second half of 2024. Combined, these new indications, along with the currently approved indications for solriamfetol, represent over 80 million U.S. patients and support its blockbuster potential. Over the course of the morning, we will have the honor to hear from our expert clinicians and scientists, who will discuss relevant pharmacology, clinical indications, and data generated to date. It is now my pleasure to turn the floor over to Dr. Craig Chepke to discuss the trace amine signaling system and basis for exploring solriamfetol in major depressive disorder. Dr. Chepke, thank you for joining us today, and please go ahead. Hi, my name is Dr. Craig Chepke. I'm an Adjunct Associate Professor of Psychiatry for Atrium Health and the Medical Director of Excel Psychiatric Associates in Huntersville, North Carolina. I want to start with a brief overview of solriamfetol. It was initially developed as a DNRI, a dual-acting dopamine and norepinephrine reuptake inhibitor with weight-promoting effects. It was approved in 2019 by the U.S. FDA and 2020 by the EMA to improve wakefulness in adults with excessive daytime sleepiness due to either narcolepsy or obstructive sleep apnea. However, it was recently discovered that it also has TAAR1 and serotonin 1A agonist activity, and some preclinical evidence supports the exploration of this medication in new neuropsychiatric conditions. There's also clinical and preclinical evidence to suggest the potential utility of TAAR1 agonists in several psychiatric and neurological disorders. Let's talk about what is TAAR1. The story starts with the trace amines. Now, trace amines have been known about for at least a century, but they were thought to be just incidental metabolites, monoamines, or just kind of worthless molecules floating around in the body. As you can see from the figure on the left, they are structurally related to the monoamines, but they're found at much lower concentrations in the brain, which led to that perception of them not being useful. You can see from the left, the column of that figure to the right, just how similar the trace amines are to the monoamines. It wasn't until 2001, when the trace amine-associated receptors, or the TAARs, were discovered, that it was realized that the trace amines do likely have important neurobiological roles. So the TAARs are activated by the trace amines, and there are 26 known TAAR receptors at this point. There may be more that we're not aware of yet, and at this point, we have found that humans express just six of these TAAR receptors. The TAAR1 specifically is the best studied, and that's because it's believed to be relevant to possibly neuropsychiatric conditions. In terms of TAAR1's believed function, we think that it can adaptively modulate neurotransmitters. So TAAR1 is expressed both pre and postsynaptically. The figure on the right demonstrates dopamine presynaptic and postsynaptic neurons. The expression of TAAR1 is usually intracellular, which led to the difficulty in discovering it. Anything that's on the cell membrane, it's a lot easier to find than something that is intracellular. However, TAAR1, when bound by a TAAR1 agonist, is able to actually form a dimer with some of the receptors, including, as pictured here, the dopamine two receptor, and it does translocate to the cell membrane, and it's able to modulate the activity of the dopamine two receptor in that regard. So, this can have some ability to modulate the function of dopamine in certain pathways in the brain. And as I said, the word adaptive is very important because the adaptive nature of it makes it able to potentially tone down dopamine circuits that are overactive, but also can increase the activity of dopamine circuits that are underactive.... and that adaptive modulation gives it a broader potential to operate with different neuropsychiatric conditions. Now, the TAAR1 also has been shown from preclinical models to regulate glutamate circuits and also to modulate serotonin activity. And also, TAAR1 is expressed in various areas of the brain that we believe and have very good evidence to support importance in neuropsychiatric disorders. So for instance, the ventral tegmental area and the substantia nigra, very important dopamine cell body locations are found there. The dorsal raphe is the site of a number of the serotonin cell bodies, and then in the prefrontal cortex. The prefrontal cortex is an area that is very rich in glutamatergic neurons and is also believed to be a primary site where executive functioning and cognition have important levels of control from. Then the limbic areas of the brain, the amygdala, hippocampus, the hypothalamus, and then also the BNST, are very important in a number of different psychiatric conditions because it, it is believed to regulate certain aspects of motivation, reward, and mood as well. TAAR1 agonists have been shown in preclinical models to have a number of wide-ranging effects. So for instance, in antipsychotic models, it potentiates the antipsychotic effects on amphetamine-induced hyperactivity and actually reduces some of the motor side effects from haloperidol. Procognitive effects have been seen in terms of improving the attentional set, shifting in rodents and object retrieval in primates. Metabolic effects, I think, are really interesting. So the TAAR1 agonism has been shown in preclinical models to increase satiety, to decrease food intake, decrease body weight, and actually, the mechanism by which it does so looks very similar to, as conceptually at least, the GLP-1 receptor agonist, so, which is obviously one of the hottest topics in the medical field today. Shifting to the right side of the graph, in antidepressant models, the forced swim tests and tail suspension tests have been seen to be improved by TAAR1 agonists. In addiction models, there's been a reduction in cocaine, methamphetamine, and nicotine addictive behaviors and food reward. And as I mentioned in the previous slide, then the reward, we believe, is in the limbic system, and TAAR1 is highly enriched in the limbic region of the brain. And then finally, in terms of wake promotion, there's been wake-promoting effects and REM suppression seen in both rodents and primates. And another neurotransmitter receptor that I think is important to discuss is serotonin 1A. So serotonin 1A is pretty widely distributed in the central nervous system, including the cerebral cortex, hippocampus, amygdala, raphe nucleus, and it not only has functions on serotonin, but also has downstream effects on modulating other neurotransmitter systems, including norepinephrine and dopamine. For instance, serotonin 1A agonism or partial agonism can, by a downstream circuit, release dopamine into that prefrontal cortex. And then serotonin 1A activation may also modulate mood, reward, and addictive behaviors, and things like food intake and cognitive function. And a really interesting fact is that TAAR1 agonism could have a synergy with serotonin 1A agonist. So if there is the presence of both TAAR1 and serotonin 1A agonism, they can be synergistic and have a greater potency than just the serotonin 1A agonist alone. In terms of TAAR1 agonists in clinical development, one is solriamfetol, as mentioned before, the DNRI, but also with, now we know, TAAR1 and serotonin 1A agonist activity. So as of today, it's the only commercially available TAAR1 agonist, as mentioned, for the treatment of EDS and OSA or narcolepsy in adults. Ralmitaront by Roche is a TAAR1 partial agonist that was evaluated in two phase II studies in schizophrenia and schizoaffective disorder, but unfortunately, both of those were terminated due to inadequate efficacy. And the last one is ulotaront by Sumitomo and Otsuka. It's a TAAR1 agonist, which does have serotonin 1A agonist activity as well, and it's currently under clinical development for the treatment of schizophrenia, generalized anxiety disorder, and adjunctive major depressive disorder, all in adults. There have been other TAAR1 agonists that have been studied preclinically, a number of them, in fact, but none have reached human clinical trials other than the, the three that have been listed. If we look at the binding affinities for solriamfetol, we can see the dopamine and norepinephrine over to the right, but really focusing on that TAAR1. The binding affinity is 10-16, so it's in... The potency for the human TAAR1 is in the m- kind of the moderate range, and it has an Emax of 100%, indicating that it is a full agonist at TAAR1. And then for serotonin 1A, it is a little bit lower potency for 1A, but still in the immediate or moderate range. This distinguishes it from compounds like modafinil and bupropion, which have neither serotonin 1A or TAAR1 activity. Psychostimulants are well known and have been for quite some time to be agonists of TAAR1, but modafinil and, of course, bupropion do not. And not just does it have binding affinity and have some potency there, this slide shows an experiment indicating that it actually has some activity that is comparable, at least, to a known TAAR1 agonist, in this case, RO5256390. So both compounds, when administered, were able to inhibit the VTA neuron firing in a dose-dependent fashion. So this is an interesting finding, showing that it does have some activity consistent with a known TAAR1 agonist. But does the medication solriamfetol at the doses at which it's clinically being used, either currently or in investigational studies, does it have clinically relevant activity?... See that solriamfetol does activate the human TAAR1 and serotonin 1A in vitro at the plasma concentrations that we believe are clinically relevant. So that would be the same plasma levels as the inhibition of the dopamine norepinephrine transporters. So we do believe that there is a good reason to believe that TAAR1 and serotonin 1A activity could contribute to the effects of solriamfetol. And I mentioned that TAAR1 and serotonin 1A agonists have applications in a broad range of psychiatric and neurological disorders. So pictured currently are the indications which were studied by companies other than Axsome, and for schizophrenia, Parkinson's disease, psychosis, generalized anxiety disorder, and MDD as an adjunct. Turning to solriamfetol, we have the EDS due to OSA or narcolepsy, which is already approved indication in the United States and Europe, also being studied for shift work disorder. Binge eating disorder is another investigational diagnosis being looked at, and ADHD as well. But on top of that, as has been discussed today, solriamfetol also is being studied now for major depressive disorder, and this is as a monotherapy, and I'll talk about the study design in just a minute or two. Turning, though, to talk about major depressive disorder in general, MDD is an incredibly serious condition. It's very highly prevalent. About one out of five individuals will experience MDD at some point in their life, which really makes it a condition that touches everyone's life by some degree of separation, really. It is also a highly debilitating disorder. Worldwide, major depressive disorder is the number one cause of disability, in fact, according to the World Health Organization. In looking at the diagnosis, it is highly heterogeneous. The nine symptoms by the DSM-5-TR are listed there. People have to meet at least five out of those nine. Some quick math shows, as is indicated over to the right, 227 unique symptom profiles that will give the diagnosis of MDD. So not only does this make it highly heterogeneous, it makes it difficult for us to treat because there's so many different symptom profiles. One agent is never going to be able to treat everyone. The unmet needs that do exist with the current treatment armamentarium is, are things like that the efficacy is usually delayed by a number of weeks, four to six, six to eight weeks. And then even for people who do achieve efficacy, it's often incomplete. They often have partial responses, and there's very often residual symptoms, and cognition is one of the common ones that is a big driver, in my experience, of disability for patients with MDD. Also, significant adverse events for people with the current armamentarium of antidepressants. The three that I think are the most troublesome, I call them the deal breaker side effects, are sexual side effects, weight gain, and sedation. Those are ones that people generally, in my experience, are not willing to put up with, that if they experience those, they're usually going to discontinue the medication, whether or not they tell their healthcare provider. And this combination of incomplete efficacy, delayed efficacy, side effects, leads to high discontinuation rates. Data here is from the STAR*D study, the largest study of major depressive disorder ever conducted, and was done by the National Institutes of Mental Health in the early 2000s. And each one of these four steps was over 12 weeks long and included a broad range of different treatments: SSRIs, SNRIs, lithium, thyroid hormone, tricyclic antidepressants, MAOIs, combinations of different antidepressants, and also psychotherapy in the form of cognitive therapy. With each step in treatment, you can see in the green bars, there's a decline of the rates of remission, and it drops off pretty precipitously. It doesn't start off very high either, at just 36.8%. With each treatment step, there's a diminishing returns in terms of efficacy, but also with the red bars that are incrementing upwards with each step, an increase in the rates of discontinuation due to side effects. Remission rates go down, and intolerability goes up each time that we prescribe an antidepressant to a patient. The bottom line is that after four lines of treatment, which is almost a year, with those four steps being at least 12 weeks long, then a third of patients still don't achieve remission. Remission is the absolute goal in major depressive disorder, as it... or at least it should be, as it is in other fields. No one would argue that in oncology, that remission is the end, is the ultimate endpoint, and that's what we should be going for in MDD as well. And part of that is that we know that people who do have residual symptoms have much greater rates of relapse and faster relapse. There have been a number of studies which have shown that. STAR*D is one of them, but there are several others which show that those who achieve remission have improved function, their prognosis is better, and have a lower risk of relapse compared to those who have not remitted. Going back to TAAR1 agonists, and why do we believe that this might be potentially beneficial in MDD? This is data from ulotaront SEP-856. It was abbreviated here on the slide, that the mice were administered either duloxetine, SEP-856, or the co-administration of the two in two different models. The FST is the forced swim test, TST is the tail suspension test, and these are both models of MDD, which are usually able to reliably predict antidepressant efficacy. In both models, we see that there was a synergistic result, that there was some effect from either duloxetine or SEP-856, but the combination of the two, especially at the higher dosages, showed a synergistic effect. So very interesting results there, indicating the potential for TAAR1 agonists in MDD. Also, the theoretical MOA of TAAR1 agonist in MDD is really complicated, as this slide shows. I annotated it with some red arrows and circles here to try to highlight out the important points. The TAAR1 agonist downstream can have a couple effects that have the endpoint down at the bottom of the slide. I circled ATP. An increase in ATP is—ATP is the fundamental currency of energy in the cells in mitochondria. So that could be very important. And then, over to the left, then a possible increase in neuroplasticity via the mTORC1 receptor, leading to an increase in the BDNF, the brain-derived neurotrophic factor. And neuroplasticity is an incredibly important topic, which we think increasingly is one of the core deficits in people who are living with MDD in terms of the potential pathophysiology. And treatments which can affect the neuroplasticity in a positive fashion are potentially incredibly important for the treatment of major depressive disorder. So we think that that TAAR1 agonism could downstream lead to the increased neuroplasticity, and we do know that there are other treatments for MDD which potentiate that pathway as well. Looking at a high-level summary of TAAR1 MOA and how it interfaces with MDD, up in the cognitive behavioral level, that there could be potentially improvements in cognitive control problems that people with MDD have, as well as the reward dysfunction. This is coming from the enrichment of TAAR1 in the prefrontal cortex and the limbic system, as we discussed earlier. On the neurobiological level, just got done telling you about the potential benefits in terms of neuroplasticity. Also, we talked about the abnormal firing rates of neurons, not just the, the dopamine, the serotonin, and potentially glutamate, neurons as well. And then metabolic dysfunction with the the conceptually GLP-1-like possible effects that have been seen in preclinical models of TAAR1 agonists. And this is important because while MDD is a serious brain condition, it's also a serious physical condition as well. There are a number of different well-validated theories of inflammation in major depressive disorder and in other neuropsychiatric conditions. Also, the inflammation may come from things like obesity, which we know that obesity and metabolic disturbances are part of MDD, as well as other neuropsychiatric conditions as well. And unfortunately, we often pour fuel on the fire by giving medications, which can worsen some of those metabolic dysfunctions and having medications which may not only not have a detrimental effect, but which could theoretically have a potentially positive effect, could be incredibly important. Looking at the trial design for Axsome's phase III trial of solriamfetol in MDD, there is going to be a five-week screening period, after which a 1:1 randomization is going to occur into either a placebo arm or a solriamfetol arm. There's gonna be a six-week treatment period with a dose titration of 75 mg for the first three days, 150 mg for days four through seven, and then 300 mg thereafter for days eight through 43. And then at the end of that six-week period, there'll be a one-week follow-up period. Inclusion criteria are that the people have to, of course, meet DSM criteria for MDD and have a MADRS score of at least 25 and a CGI-S score of at least fourth, both at screening and at the baseline. Primary endpoint is going to be the safety measures, including the adverse events, treatment-emergent adverse events, the ECG readings, and the Columbia-Suicide Severity Rating Scale. So our key takeaways here for the TAAR1 MOA in major depressive disorder, medications that have TAAR1 and serotonin 1A agonism together are really compelling in terms of drug development as a target in neuropsychiatry. There's been a lot of potential shown in this arena, and so we're looking forward to seeing, clinical trial results to hopefully bear that out. Solriamfetol as of now is the, only commercially available TAAR1 agonist and does have potential in multiple new target indications, and really in part because of its recently uncovered TAAR1 and serotonin 1A agonist activity on top of the NDRI activity that we already knew that it had. In MDD, cognitive deficits are often a major driver of the disability in MDD and are often residual symptoms even after some of the emotional symptoms have been treated. Based off the mechanism of action, solriamfetol could have cognitive benefits in major depressive disorder, we may be able to theorize. Having the multiple broad spectrum mechanisms of action that solriamfetol is believed to have, including norepinephrine reuptake inhibition, dopamine reuptake inhibition, and serotonin 1A agonism, along with that TAAR1 agonism, could be potentially beneficial for a really broad range of patients, including those that have not been well served by the traditional antidepressants. In terms of tolerability, the tolerability profile of solriamfetol is very well characterized at this point from the numerous clinical trials it's been through and is not associated with the adverse reactions that are considered to be the most bothersome, often for people with MDD. Those are the deal breaker side effects I mentioned of weight gain, sexual dysfunction, and sedation. So I want to thank everyone for the attention today and look forward to hearing the rest of it. Thank you, Dr. Chepke. It is now my pleasure to introduce Dr. Andrew Cutler, who will provide an overview of attention-deficit hyperactivity disorder, or ADHD. Dr. Cutler, thank you for joining us today, and please go ahead. Hello, this is Dr. Andrew Cutler. I'm a clinical associate professor of psychiatry at SUNY Upstate Medical University, and I'm here to talk about attention-deficit hyperactivity disorder, or ADHD. ADHD, the diagnostic criteria from the DSM-5, require a certain number of symptoms. There are 18 potential symptoms of ADHD, and they divide into two categories. We have nine symptoms of inattention and nine symptoms of hyperactivity, impulsivity. Symptoms need to be present for at least six months, and for patients under the age of 17, they have to have six or more symptoms from either or both of those categories of nine symptoms. For adults, the symptom threshold has been lowered to five because as people age, sometimes these symptoms get a little better or you can compensate. Now, the symptoms have to occur in more than one setting. They have to be present before the age of 12, so this is a neurodevelopmental disorder that starts, we believe, in childhood. Again, highly genetic, so you're probably born with this condition for the majority of patients. ... Symptoms must, of course, cause impairment and can't be better explained by other symptoms. Now, ADHD, I mentioned, is very common, and, there's at least, and probably more than this, but at least 17.5 million people in the U.S., and the prevalence is similar around the world. I've presented at meetings all around the world. We know that the prevalence is in the 8%-10% range, and we also know that we used to think of this predominantly as a childhood disorder and that you outgrow it. However, newer research suggests, no, that's not true. Over 90% of the time, it persists into adulthood, but it can wax and wane depending on environmental stressors and changes, because adults can learn compensating mechanisms, and they can choose environments and careers that play more to their strengths. So, this is very important. Another important point is significant comorbidity with ADHD, including depression and anxiety, and substance abuse. Now, I mentioned that ADHD is genetic and has a neurologic basis. We've learned a lot from neuroimaging studies that there are abnormalities in the brains of people with ADHD. Predominantly, that has to do with how parts of the brain communicate with each other and connect. We have certain networks, and circuits in our brain of how parts of the brain talk to each other, and part of how this communication happens is through monoamine neurotransmitters such as norepinephrine and dopamine, and they've been shown to be abnormal in patients with ADHD, and so most of our treatments do work through norepinephrine or dopamine. We think of the brain as working in a top-down, bottom-up sort of way. So the top of the brain, the cortex, is where higher functions are, including executive function, which is planning and organizing and evaluating information that comes into the brain. Lower parts of the brain, the limbic system, have to do with emotional regulation, sensing threat, and things like that. We know there are underactivation of some of these networks, including frontostriatal, which is top-down, and frontoparietal, which is the front part of the brain talking to various attention centers in the brain, and so there's impaired goal-directed executive process. We also know there's abnormalities in emotional regulation, which is sensing threats in the environment, processing emotional information. Is this important? Do I need to overreact to this or not? How important is the information coming into me? Do I need to deal with it right now, or can I file it away for later? Also, significant problems with what we call the motivation reward network, which is evaluating the importance and the potential reward of things. And people with ADHD have significant problem with delaying gratification and with evaluating the potential gratification in the future of things. Also, we have a lot of problems with paying attention, with paying attention and sustaining attention. So a, the name attention deficit disorder is really a misnomer because people with ADHD can pay attention if something is really interesting to them. The problem is if it's not, they can't sustain attention. So it's really an attention regulation disorder, kind of an all or none situation. All right, now, we do have, of course, FDA-approved treatments. The most effective and most prescribed treatments are the stimulants, which are methylphenidate and amphetamine, which are short-acting molecules by themselves. So most of the development in ADHD medicine over the past 20 years has been in technologies and formulations to extend the duration of action of these stimulants from three to four hours out to all day, even up to 16 hours, if possible. There also are, besides pills, liquids, chewables, and patches now available. As far as non-approved stimulants, and this is where a big unmet need lies, there are only four FDA-approved, and of those four, only two are approved for adults, and those are atomoxetine and viloxazine extended-release. Atomoxetine is a norepinephrine reuptake inhibitor. Viloxazine is also a norepinephrine reuptake inhibitor and binds to three specific serotonin receptors, 5-HT2A, 2B, and 2C. Viloxazine was an effective antidepressant in Europe, so in addition to working for ADHD, it may have effects on some of those comorbidities of depression and anxiety. There are two alpha-two agonists, which have been approved for hypertension, but in extended-release form, guanfacine and clonidine are also effective for ADHD. We know there's a very high discontinuation rate. This is high for all psychiatric disorders, but especially for ADHD medications. There are many reasons for this, including poor insight on the patient's part, stigma, the fact that stimulants are very difficult to prescribe and to get at pharmacies and things have many restrictions on prescribing and so on. Now, as far as the treatments and the unmet need, as I mentioned, stimulants are the most effective, but they have the most baggage and risk. They are Schedule II, high potential for abuse, and they have significant side effects, including and risk, including cardiovascular, neurological, gastrointestinal, insomnia. When they wear off, you can get a significant rebound phenomenon with irritability and so on. Also, there's the risk with stimulants of blunting someone's personality. Non-stimulants, less effective, and there are certain side effects for clonidine and guanfacine. They're very sedating, so it's hard to use by themselves. We often add them, and they're not approved for adults. Atomoxetine and viloxazine have black box warnings around suicidality, but can be effective, as I said, in some patients. Now, we need newer mechanisms, and what the world really needs are more non-stimulant options, especially effective ones. The mechanism of action of solriamfetol, to me, predicts that it should be effective for ADHD by virtue of being a dopamine and norepinephrine reuptake inhibitor, which overlaps with the mechanism of stimulants. However, as we know, solriamfetol is not considered a stimulant, and it is not Schedule II. It is Schedule IV, meaning low, low to no significant abuse potential. Also, the TAAR1 mechanism is fascinating to me. We've heard about the trace amine-associated receptor type one, because stimulating that receptor can regulate neurotransmitters, including glutamate and the monoamines, norepinephrine, dopamine, serotonin, which predicts there could be some benefit in some of those comorbidities I mentioned earlier. The problems with all of our medications are they may not work as well for emotional dysregulation and for executive dysfunction, and stimulants can actually worsen some of the comorbidities, including anxiety and possibly depression. Now, we do have a pilot study. We have some data already for solriamfetol for ADHD in adults. This was done by my friend Craig Surman at Harvard University, and this was what we would consider a pilot study, a relatively smaller study with 60 patients, but still a good number. This is a six-week trial. Patients started on solriamfetol, 75 milligrams for two weeks, and it was titrated up to 150 milligrams. You can see here 60 patients, about half solriamfetol, about half placebo. Very standard rating scales. The primary measure was called the AISRS, the Adult ADHD Investigator Symptom Rating Scale. That simply measures the 18 symptoms of ADHD that I mentioned earlier in the DSM, and you get a total score. Higher is worse, of course. The secondary is called the Clinical Global Impression or CGI. This is not rating specific symptoms, but the clinician's overall impression of how the patient is doing. Various secondary measures, very important here, included a measure of function, patient self-report, also something called the BRIEF, which measures executive function, and the Pittsburgh Sleep Quality Index, which measures, of course, sleep and insomnia, and the Epworth Sleepiness Scale for sedation in the day. As you can see here from the results, very significant efficacy for solriamfetol at decreasing ADHD symptoms measured by that AISRS scale. And this was highly significant relative to placebo, with an effect size of about one, which is what you expect from stimulants. Now, I want to be careful and say this needs to be replicated, and it is being studied in phase III, but it's very exciting preliminary data. And I want to point out the clinical meaningfulness of this data. You can see here that at the endpoint, on average, the patients on solriamfetol, their AISRS score was around 18, and that's a cutoff we use for symptomatic remission of ADHD, meaning that the patient would actually no longer qualify for the diagnosis. Of course, we're not curing this disease, we're managing it. Whereas those on placebo, their scores were still in the 20s, meaning at least moderate symptomatology, and they would qualify for the study at the end of the study with placebo. Other secondary measures were all consistent with this, all showing improvement with solriamfetol, including that CGI, the overall clinical impression. And you can see, using that measure, approximately half of these patients were judged to be much or very much improved, compared to only around 7% on placebo. Highly clinically meaningful data. Now, as far as tolerability, the most important thing to mention is nobody stopped taking the medication due to side effects. So while there were a higher rate of side effects with solriamfetol versus placebo, in general, patients didn't judge them to be serious enough. They didn't vote with their feet by stopping the medicine. The side effects that we're seeing here, with a max dose of 150 milligrams, were consistent with those seen in the other studies and included things like decreased appetite, headache, some gastrointestinal-type side effects, as well. So, this study was very encouraging and really supported going further with the development of solriamfetol for ADHD. As I mentioned, there is a phase III trial that is underway right now. This is for adults with ADHD who are 18-55 years old, and it's a six-week study comparing two doses of solriamfetol, 150 mg and 300 mg versus placebo. I think it's important to mention that in the excessive daytime sleepiness studies that were done, there did appear to be a dose relationship with higher doses of solriamfetol working better. And so this will be very helpful to see if a 300 mg dose is effective and even has evidence of better effect than the 150. That would be very important to support the approval. And the target here is 450 patients, which is a fairly large study. And this study, clearly, I've been doing ADHD studies for almost 30 years, and this is a study that, uh, really looks like the studies that are done to support approval of a medication. All right. Finally, I'd like to summarize by saying ADHD is very common, it's highly impairing, and it has significant comorbidities. It has a higher rate of mortality, especially with comorbidity, from things like accidents, cardiovascular disease, and sadly, suicide. Most common comorbidities are depression and anxiety. Causes significant impairment, as I mentioned, and it is seen across the age spectrum. We have medications approved, but there are still significant unmet needs for an effective non-stimulant medication that perhaps can also help with some of the comorbidities and the functional impairments seen with ADHD.... So solriamfetol is differentiated. It has a different mechanism, although it shares the dopamine, norepinephrine, reuptake inhibition, potentially with some of the others. It also has the TAAR1 agonism, which we mentioned, which means it might work for some patients who don't do as well with others. Tolerability profile is well characterized, and one of the nice things is it's already on the market. It's already gone through the DEA scheduling process and has been found to have low abuse potential and is a Schedule IV, which is a lot easier for myself and my colleagues to prescribe and a lot easier for patients to get and to take with less, potentially less stigma. It is a once a day medicine, which is certainly very important as well. So I want to thank you for your attention and looking forward to your questions. Thank you. The lines are now open for a brief question and answer session with Doctors Chepke and Cutler. We will take questions in the order they are received through the call-in number provided in the press release and on Axsome's webcast and presenters page. Our first question today is coming from Joseph Thome with TD Cowen. Please go ahead. Hi there. Good morning, and thank you for taking my question. Maybe just one on the major depressive study that's going to be initiating for the phase III. Just given that there is that planned dose titration, can you talk a little bit about what happens if a patient can't titrate up to the next dose? And maybe what are the key AEs that you'd be looking for when advancing the patient to the next dose, given the mechanism? Thank you. Thank you very much for the question. So some of these questions I'm going to have to defer to Axsome in terms of the study design, in terms of what will happen if people can't go forward with the titration. But the AEs that I would be looking for in the titration to determine tolerability would be those that we see with solriamfetol in the EDS indication. Do they have any increase in the anxiety? Do they have any increase in any other adverse reactions that could be indicating excessive stimulation and gastrointestinal side effects? Things that were looked at again in the EDS studies. So I would expect it to be similar in the MDD population, that what we would be interested in. In terms of the clinical trial design, I would defer that to the Axsome team. Yeah, and I would also add, in studies of other TAAR1 agonists, they've been extremely well tolerated. Joseph, did you have any additional questions? Yep, and then maybe just second, on the ADHD indication. I know you mentioned that 18-point cutoff, but is there anything else in the data set for the adults that we might see next year that you would deem clinically meaningful? Is there a certain proportion of patients reaching that 18-point goal, or is there a delta versus placebo on the AISRS that you, that would make you particularly excited? How, what are you looking for in that data, I guess? Yeah, absolutely. I mean, one of the things I look for is balanced efficacy. So the ADHD rating scale we use does allow us to look at the cluster of inattention symptoms and hyperactive impulsive. So I'd like to see efficacy in both areas. I'd like to look at response rates, and there's various ways that you look at a response rate, but I'd like to see the percentage of patients showing a response, not just the average response, if you will. I'd caution everybody that an effect size in the one range is not a reasonable expectation here. You know, the study I presented was a pilot study, small study, excuse me, and effect sizes of one are what we see with stimulants. If it does approach one, if it was in the 0.6-0.8 range, that would be terrific. I'd be thrilled. But I just want to moderate expectations a little bit. You know, one of the things that's important is ADHD, like depression, is probably a very heterogeneous condition, biologically and clinically. And so to think that just one mechanism or one kind of medication is going to work for everybody, of course, is silly. So having another drug with a differentiated mechanism like this, and I didn't talk really about the 5-HT1A receptor. I mean, there's a lot of evidence that agonism at that receptor increases dopamine into the prefrontal cortex, may have procognitive, antidepressant, and even anti-anxiety efficacy. There are drugs on the market already with 5-HT1A agonism, and that's what's been seen. So I don't want to overpromise that, but those are the kind of things I'd be looking for. And then, of course, secondary measures that would include a patient's self-report, quality of life, executive function, and so on. Perfect. Thank you very much. Thank you. The next question is from Richard Nguyen of Mizuho. Please go ahead. Hi, good morning. Thank you for taking my question. I'm on the call for Graig Suvannavejh. So just a question from me on expectations. Again, I think you mentioned that you're looking for efficacy and the response rates for ADHD. What% would be good there? And then, two, Dr. Chepke, I just want I just want to get your impression of how solriamfetol compares to other TAAR1 agonists and how you would position solriamfetol versus other TAAR1 agonists. Thank you. Okay, well, real briefly, it depends on how you look at the response rate. One way is that people look at the Clinical Global Impression, CGI, and we look at the percentage of patients that are judged to be much or very much improved, and in that, on that measure, I'd look for a 50%-60% response rate. That would certainly be good. And there's various other ways you can do it, but that's one of the main ways. In terms of the question for me, I would say this is a very different looking molecule than the other TAAR1 agonists that are in clinical development. Ulotaront, for instance, is really primarily just a serotonin 1A and TAAR1 agonist and does not have really meaningful potency at other receptors, whereas solriamfetol has the TAAR1 and 5-HT1 agonism, but also has the dopamine and norepinephrine reuptake inhibition. So it has a different set of receptor binding profiles and the potencies as well as the neurotransmitters. I think that there's quite a bit of differentiation, and I would welcome there to be multiple medications with TAAR1 agonism available to prescribe as a clinician, so we can try to treat the broadest spectrum of patients possible. Thank you. The next question is coming from Joon Lee of Truist Securities. Please go ahead. Hi, thanks for taking our questions. I have one for management and one for the KOLs. For the management, what's the business rationale for advancing solriamfetol and MDD, as opposed to other indications such as schizophrenia or generalized anxiety disorder, especially when you have already, when you're already marketing Auvelity for MDD? How would you position these drugs in MDD? And for the KOLs, you know, solriamfetol seems to have many beneficial properties, but does the fact that it works in EDS, ADHD, MDD, and BD a big concern that you may potentially be over-treating the patient? Wouldn't clinicians want a more targeted drug for specific indications? Thank you very much. Sure. Hi, June. The question to management. With regards to selecting MDD as one of the indications, one of the things that we've learned from our KOLs and from other clinicians is the wide variability in terms of symptomatology for patients who have MDD. And what we've been always interested in, in Axsome, is providing new mechanisms of action to treat MDD. And so moving away from just the traditional monoamines. So, you know, with Auvelity, we introduced the first oral NMDA receptor antagonist. And so if solriamfetol does have activity in MDD, in the trial that we plan to conduct, then this would represent another new mechanism of action to treat MDD. Perhaps our expert panel has, you know, their perspectives. Yeah. Craig, if you don't mind, I'm gonna start. I just want to say what a pleasure it is to be on the call with my good friend and colleague, Craig Chepke. I see the question too, and I would say, going back to what I said earlier, there's a very heterogeneous disease, not only neurobiologically, but with the clinical symptoms, the clinical presentations. And we're finding, you know, some patients do better with one kind of medicine than another. So I think this is such a differentiated mechanism from Auvelity that as a clinician, I would love to have this in my armamentarium. Now, as far as the question about over-treating and the indications, I want to quickly say first, I don't see this as a schizophrenia medication for a number of reasons. One is, it probably does not have high enough potency or binding at TAAR1. You have to bind TAAR1 pretty tightly to get the antipsychotic effect. But as far as over-treating, I think Craig probably is smiling there because we know how comorbid these conditions are. With ADHD, the most common comorbidities are anxiety and depression. Binge eating disorder is more common in ADHD and vice versa. In patients with binge eating disorder, ADHD is quite common. I have a lot of clinical and research experience in that area. So I think that it's actually better to have one medicine that can treat several things, because most of our patients end up on more than one medicine to treat these comorbidities. Craig? Well, Andy, you've known me long, so long that you correctly predicted I was smiling, and you gave almost the same answer that I was going to give as well. Our diagnostic categories are really fairly arbitrary in psychiatry. They're not based off of blood tests, DNA, scans, as in other fields of medicine, and as a result, there is substantial overlap. And so that leads to both diagnostic confusion and also to true comorbidity. So generally, clinicians really do welcome one medication that is able to treat a pretty broad spectrum of symptoms, especially when they are often comorbid with each other, because no one likes to prescribe polypharmacy, and no one likes to take polypharmacy, but often we have to do what we have to do. Having a medication that is able to treat a number of the comorbidities that these patients are living with, that to me is generally a pretty strong advantage. Those are, those are really helpful insights. About what proportion of MDD patients do you think have comorbid something else, like ADHD or EDS or VD? Very high. Disorder. Very high. Yeah, the majority, over half. Yeah, I think we would agree. Excellent. Thank you very much. As far as ADHD, 80% of patients with ADHD had comorbidities. Thank you. The next question is coming from David Amsellem of Piper Sandler. Please go ahead. Thank you. I had a couple questions for Dr. Cutler. So with the stimulants really dominating the ADHD treatment landscape historically, can you talk to the extent to which solriamfetol really could cut into your usage of stimulants- Yeah. Broadly speaking? Mm-hmm. And then the second question is- ...Would you consider combining solriamfetol with stimulant and dosing a patient, on a stimulant at a lower dose so as to get a better tolerability profile for the stimulant and maybe better, efficacy overall for the patient? How do you think about that? Thank you. Well, if you don't mind, I'm going to start with the second question and say, "Amen, brother!" And exclamation point. I would absolutely do that. As far as the first question, and the second question is for relatively obvious reasons. A very common thing we prescribe is a stimulant plus an SSRI to deal with comorbidity. And here, if I have one medicine that can handle ADHD and depression, let's say. As far as the other question, I think one of the nice, there's two things going on that Axsome can really hook into some momentum here. The first is, the prescribing of stimulants has become exponentially more difficult as people are afraid this is going to become the next opiate crisis. So every state now is enacting more restrictions. In my state, in Florida, for instance, I have to check the prescribing database for every patient, for every prescription of stimulants I write, which is pretty onerous. I can only give a one-month supply, can't give refills, can't call it in, fax it in, if you will. So there's a lot of, of real restrictions. There's a lot of stigma around stimulants. So number one is there's a lot of momentum towards non-stimulants. Number two is we have now, a couple of companies. We've got, obviously, Viloxazine XR, which is being heavily promoted. We have, centanafidine. Otsuka is getting ready to launch, and so they'll be a player here, marketing. So I think there'll be a, a lot more promotion and education around non-stimulants. So I think that this would be just hooking into a terrific, wave, if you will, a lot of momentum to, you know, have good alternatives to stimulants, I would say. Craig, would you agree? Craig's also an expert on ADHD, by the way. Yeah, I totally agree. In terms of the second question, the kind of a harm reduction model of using solriamfetol to decrease stimulant dosages, I already have lots of experience with that in excessive daytime sleepiness due to either sleep apnea or narcolepsy. I see a large portion of that population, and that's what I've done with many patients, is that they are often prescribed in an off-label fashion the psychostimulants, and they have certain tolerability issues and certain efficacy difficulties as well, sometimes. Utilizing solriamfetol there has been able to do that successfully. So I think that's a fantastic idea, like Andy said, and definitely, I think the overall... Well, yeah, more or less, I agree with what my friend Andy said. That's very helpful. Thank you. Thank you. We're showing time for two additional questioners for this Q&A session. The next question is coming from Myles Minter of William Blair. Please go ahead. Hey, thanks for taking the question. Maybe a question for both of the docs. Pretty confident that you're going to be using this therapy if it shows good clinical data, as an adjunct or as a monotherapy, you'd be pretty flexible. Seems like this solriamfetol does require some sort of titration period. So my question is, like, regardless of the background, anti, antidepressant or ADHD drug stimulants, like, is that going to be uniform? And how comfortable would you be titrating on the background therapy without the clinical data, in the public arena? Thanks. I'm going to let Craig start on this one. Sure. So yeah, as you're pointing out, the clinical data is looking at monotherapy, but we know that in the real world, that many times there is polypharmacy and that certainly we do cross titrations to get from one medication to another, and in many cases, patients get stuck, as we say, in between that cross titrations. They end up on dosages of both. And I think for me, the nice thing is that at least for the maybe MDD population, for the vast majority of people who are on SSRIs, there's not going to be a substantial overlap of the mechanisms of action. There's not a significant SSRI component of solriamfetol, so there would be... That would alleviate a lot of the fears. And also, we know that the most common combination of antidepressants that is prescribed in the real world is an off-label one, which is bupropion on top of an SSRI, which an NDRI with an SSRI. So, bupropion, however, as demonstrated, did not have any of the serotonin 1A or TAAR1 agonism, but again, it's not overlapping mechanisms of action, so I would not have a strong clinical fear of there being tolerability issues from that regard. And then in terms of ADHD, again, if the potency for solriamfetol in dopamine and norepinephrine reuptake inhibition is much, much less than those for the psychostimulants. And so I wouldn't have too many concerns there, because if there's a dopamine and norepinephrine reuptake pump, then it's going to be the stimulant binding it, not solriamfetol, and it would be the differentiator would be that TAAR1 and serotonin 1A, which again, I wouldn't have concerns with the tolerability there. I think it has the potential to fill in the efficacy gaps, both in the primary indication and potentially for some of those comorbidities, as we discussed. So I'd be personally extraordinarily comfortable doing it. Yeah, and I would add that the potency at the dopamine and norepinephrine transporters is actually quite a bit higher than bupropion, and it is a DNRI, whereas bupropion is an NDRI. I mean, it does have a little more affinity for the dopamine transporter than the norepinephrine transporter. I am not-- we're not afraid. As a matter of fact, we embrace drugs with titrations. I also think it's very valuable to have a range of doses approved. There's no such thing as one size fits all, and I think a lot of our colleagues would like having that kind of flexibility. So I would agree completely with Craig and say that titration and overlap, for all the reasons we're saying, they're not an issue. ... Thanks for the question. Thank you. The next question is coming from Matt Kaplan of Ladenburg Thalmann. Please go ahead. Hi, good morning, and thanks for taking the question. I guess, just wanted to get a little bit more detail in terms of the dosing titration in the phase III for ADHD to 300 milligrams versus the pilot study, where you dose titrated to 150 milligrams. Would you expect an increase in effect size at the higher dose? Mm-hmm. I guess the second part of the question, what is known about the tolerability profile at 300? Okay, well, I'm going to start and let Craig do the tolerability issue. I would certainly expect greater efficacy at 300 milligrams. We saw that in the excessive daytime sleepiness data, and, you know, that would be nice to have now, but these are averages. So in the real world, there are some patients who will need a higher dose and some who will tolerate the higher dose just fine. So I'm really excited, as I mentioned earlier, to see the data of 150 versus 300. As far as my friend Craig Surman's study at Harvard with the 150 milligram dose, he was using, you know, the currently FDA-approved dose, which I think is reasonable and still showed that benefit. But I'm predicting higher, more efficacy at the higher dose. Yeah, and to take over with the tolerability, if we look back to the EDS studies, then of course, the 300 milligram dose was utilized there, but it was a different dose titration. It was a much more aggressive dose titration than what's being proposed for the current set of studies. And so that dose did show a higher degree of adverse events, but I think that could very well have been related to the very aggressive titration that they're getting in there. Because, generally, in my clinical experience, it's the adverse reactions that occur very early on during the titration are the ones that are more likely to make a patient turn back and say, "No way," as opposed to, when it's slowly titrated up over time, then that usually leads to better tolerability, and the same goes through with clinical trials generally as well. So, could there be a greater adverse event profile at 300? Sure, there could be. We'll see. I think the slower titration is going to help with that, but the efficacy, I do think that there is good reason to believe that there could be greater efficacy. Discontinuations due to adverse reactions is a good proxy for the adverse event profile, because it takes into account both the patient's perceived benefit and the adverse events, the difficulty they have tolerating it, because even if there's tolerability issues, if it gives them a significant clinical benefit, that's a, for many people, good value proposition to them, so to speak. Yeah, and I would say even in the EDS studies, the 300 milligram dose, to me, looking at the adverse events and the tolerability profile, the safety was definitely acceptable to me. Yes. But I- Yeah, it definitely was not bad. I understand why. Yeah. Great. Great. Thank you. All right. Thank you. This concludes the first question-and-answer session. I will now turn the floor back over to Mark. Thank you, operator. It is now my pleasure to introduce Dr. Susan McElroy, who will provide an overview of binge eating disorder, or BED. Dr. McElroy, thank you for joining us today, and please go ahead. Hello to everybody, and thank you so much for being here and listening to our talks. I am going to be talking about why we think solriamfetol will be a really good treatment for binge eating disorder. This next slide shows my disclosures. And then okay, so the outline of my talk, I am going to provide a brief overview of binge eating disorder, the mysterious eating disorder that most people don't know about. I am then going to provide a brief overview of the treatment of binge eating disorder, and then I'm going to provide an overview for the rationale for solriamfetol in binge eating disorder. So what is a binge eating episode? It's amazing to me how many people don't understand this, when in fact, we have a very good nomenclature to define it. A binge eating episode is eating in a discrete period of time, an amount of food that is definitely larger than most people would eat during a similar period of time and under similar circumstances. Plus, people have a sense of lack of control over eating during the episode. They want to stop, but they can't. So okay, so what is that? Okay, that is a binge eating episode. What is binge eating disorder? Binge eating disorder is the most common eating disorder. You'll hear me come back to that point many times in which people have recurrent binge eating episodes. And again, I'm going to keep saying this because people can understand how somebody would lose control of their alcohol intake. People tend to understand how people could lose control of their drug intake. People understand how you can lose control of your gambling behavior. People can understand even how you might lose control of your sexual behavior, but people have an incredibly hard time understanding that people can lose control over their eating behavior. So again, BED, binge eating disorder, is characterized by binge eating, where people eat an unusually large amount of food in a discrete period of time, and they feel this, a sense of lack of control over eating. Broadly, BED is basically binge eating without inappropriate compensatory behaviors. It's incredibly common for people to think that if you have binging, you have bulimia. That is not true. So, and then the other thing I want to stress is that BED is the most common eating disorder. Even though it's the least well-recognized eating disorder, it is the most common, and it's more common than anorexia and bulimia combined. On this slide is depicting the DSM-5 criteria for binge eating disorder, and I guess there's a couple important points here. Number one, psychiatry, DSM-5 science, has incredibly careful criteria for the diagnosing of this disorder. Number two, I'll go through these criteria. So, people have recurrent binge eating episodes. Now, because the binge eating episodes are not followed by some sort of purging, like vomiting, laxative abuse, excessive exercise, as you would see in bulimia, we have these behavioral indicators of loss of control: eating until feeling uncomfortably full, eating large amounts of food when not physically hungry, eating much more rapidly than normal, eating alone because you are embarrassed about how much you're eating, and then feeling really bad about yourself for overeating. And my experience is, if somebody says yes to having binge eating episodes, where they eat a large amount of food in a short period of time, and they have a loss of control, they virtually always will have at least three or more of these behavioral indicators of loss of control. So additional characteristics, and remember, we're talking about the DSM-5 criteria for the diagnosis of BED. Somebody has to be really upset about the binge eating episodes. I would say this is a very common occurrence, but you do see patients who are binging, who are not upset by it. And I have interesting cases to talk about. So this goes to my thinking that BED is massively underdiagnosed. Okay, additional, okay, additional characteristics. So the binge eating is distressing. It is not associated with inappropriate compensatory behaviors that you would see in bulimia, such as throwing up, excessive exercise, laxative abuse. And then it cannot be due, it cannot be occurring during the course of anorexia or bulimia. Binge eating disorder is the most common eating disorder. Nearly 3% of the United States adults, 1.6% of United States adolescents, and 1.9% of people worldwide have BED. The prevalence for other eating disorders, anorexia is 0.6%, bulimia, 1%. So BED is the most common eating disorder. Now, like other eating disorders, binge eating disorder affects women more often than men, but binge eating disorder is more common in men than other eating disorders. So you see, it's not uncommon to see men with BED. What about the course of BED? It frequently presents in young to middle adulthood. It's not uncommon for it to begin in childhood. The course may be remitting, recurrent, or chronic, and I would say it's often chronic. Binge eating disorder is not a trivial disorder. It is associated with a whole host of conditions associated with morbidity. So BED is associated with other forms of overeating, such as night eating, grazing, loss of control eating. We can talk, if somebody wants to know what that is, we can talk about it afterwards. It's also associated with weight gain. And in fact, patients often seek treatment when they're having a malignant increase in their weight. BED is strongly associated with obesity, including severe obesity, defined as having a BMI of greater than or equal to 40. And it's, and as you'd expect, it's therefore also associated with, you know, a number of obesity-related conditions, type 2 diabetes being particularly important. Binge eating disorder is also associated with other psychiatric disorders, such that the majority of patients, 80%, have at least one other comorbid psychiatric disorder, including mood, anxiety, substance use, impulse control disorders. And then finally, BED is a painful disorder. It's associated with the reduced quality of life, it's associated with impairment in functioning comparable to bulimia, and it's associated with increased health, healthcare use and costs. And then, well, it's also usually associated with marked distress. People feel horrible about this. They, they don't understand why they cannot control their eating. Therefore, it, this is not a trivial disorder. This next slide shows that, most people with BED remain untreated. These are relatively older data. They're from 2007, but in my experience, they are still true today. Now, how do we treat BED? The standard of care has not yet been clearly defined. Treatments that are used include psychoeducation and self-help strategies. I think these are very helpful, but they don't always, you know, reduce the binge eating. Behavioral weight loss treatment and empirically-based psychotherapies. I think these treatments can be helpful for some people, but it's interesting how many people will stop binging, and they don't lose weight, so you wonder what that means. Pharmacotherapy, obesity surgery. These people often receive obesity surgery, and it's really unclear what obesity surgery does with these people. And then obviously, they can receive combinations of these treatments. Let me now focus on the pharmacotherapy of binge eating disorder. There's only one drug that has an FDA approval for binge eating disorder, and that's lisdexamfetamine. The data for that study were incredibly positive. Lisdexamfetamine is a stimulant prodrug. The only other drug approved for an eating disorder is fluoxetine for bulimia. Fluoxetine is, at best, modestly effective for the binge eating in both bulimia and even BED. Now, a very interesting story is, the development of dasotraline in BED as well as ADHD by Sunovion. I'll come back to that. Despite positive efficacy results, the development was halted, and I'll come back to that. So, okay, so we have one drug approved for BED. That's lisdexamfetamine, but there... You know, it's, it's clearly efficacious, but there are a number of problems, and that includes that it's addiction. It's a Schedule II drug, cardiovascular side effects. It can be mood-stabilizing, mood-- excuse me, it can be mood-destabilizing, and not everyone responds to the drug or tolerates it. So we desperately need new medications with novel mechanisms of action for BED. Okay, let me just say a little bit about dasotraline. Dasotraline is a selective dopamine norepinephrine reuptake inhibitor like solriamfetol. It was being developed for ADHD and binge eating disorder by Sunovion, and there were two highly positive registration trials for BED, but the drug was not developed further. I don't know why. Here are the data from one of the studies, and you see a marked separation between drug and placebo for reducing binge eating with a very, very impressive effect size of 0.74. So what is the rationale for using, for studying solriamfetol in BED? Okay, number one, it's a dopamine norepinephrine reuptake inhibitor like dasotraline. Number two, it's associated with reduced appetite and weight loss. And number three, which I won't go into a whole lot is that there is a very interesting link between narcolepsy and BED. And I'll just say, many people with narcolepsy also have binge eating. Many people with narcolepsy have overweight. And then drugs that work. Drugs that work in narcolepsy may work in BED, and that includes not just lisdexamfetamine, but Xyrem. I've been doing research in BED for a long, long time, and what our group has found is that drugs that affect the central nervous system, that are associated with weight loss and/or reduced appetite, that have been studied in BED in at least one randomized controlled trial, have always worked. So I think another strong rationale for the use of solriamfetol in BED is we've got some preclinical data showing that in animal models, you know, in mice and rats, it reduces food intake, and the higher the dose, the greater the reduction in food intake. Data from clinical trials of this compound in people with obstructive sleep apnea and narcolepsy show that decreased appetite was an incredibly common side effect, and there was also weight loss was also reported as a side effect as well. But I think that the data that I am particularly intrigued by are data from this 40-week outpatient trial. Excuse me, open label trial, a 40-week open label trial looking at the effects of solriamfetol on weight in people with obstructive sleep apnea or narcolepsy. And you can see an incredibly profound weight loss. This slide shows the percent of patients with a greater than 5% decrease in weight in this trial, and it's dose related. So if we look at the overall group, nearly a third of patients receiving the higher dose of solriamfetol lost at least 5% of their body weight. Okay, so this has led us to suggest that solriamfetol should be studied in binge eating disorder. Here is a schematic depicting the design of the phase III trial. It's a dose-finding study, so patients with binge eating disorder will be randomized to placebo or one of two doses of solriamfetol, 150 milligrams and 300 milligrams for 12 weeks. These are people who will have binge eating disorder by current diagnostic criteria, and the endpoint will be number of binge eating episodes as recorded by diary. Of note, the design of this trial is very similar to the design of the lisdexamfetamine and dasotraline trials in BED, all of which were frankly ridiculously positive. So to conclude, the key takeaways for solriamfetol and binge eating disorder. Number one, binge eating disorder is the most common eating disorder, affecting almost 3% of the United States population. BED is associated with a two- to threefold increased risk of psychiatric and medical comorbidities. Despite the high prevalence of the disorder and this, and the burden of this disorder, there is only one FDA-approved medication for BED. That's lisdexamfetamine and solriamfetol—so the evaluation of solriamfetol in BED is supported by its pharmacology. It's a dopamine norepinephrine reuptake inhibitor. It's preclinical effects and clinical effects in appetite and weight observed in OSA and narcolepsy patients. Thank you very much. Thank you, Dr. McElroy. I would now like to turn the call over to Dr. Richard Bogan, who will discuss the SHARP study in patients with excessive daytime sleepiness associated with obstructive sleep apnea, or OSA, and impaired cognitive function. Dr. Bogan, thank you for joining us today, and please go ahead. Hello, I'm Dr. Richard Bogan. I'm Associate Clinical Professor at the University of South Carolina School of Medicine and the Medical University of South Carolina, and a principal of Bogan Sleep Consultants. Today, I'm going to discuss the SHARP study, which is the effects of solriamfetol on cognitive function in participants with cognitive impairment associated with excessive daytime sleepiness and obstructive sleep apnea. What we know is that individuals with obstructive sleep apnea oftentimes have excessive sleepiness or non-restorative sleep. They tend to have obstruction of the upper airway, fragmented sleep, and oxidative stress. We treat them, of course, and many of those individuals, despite adequate treatment, still have daytime sleepiness, maybe as high as 28%. It varies depending upon the cohort. But patients with excessive daytime sleepiness associated with obstructive sleep apnea, despite adequate treatment, oftentimes have other symptoms of sleepiness. Sleepiness can cause fatigue, but certainly can cause executive function abnormalities, and then those executive function abnormalities may be cognition, memory, speed of processing. This is one of the reasons that we wanted to study solriamfetol in this particular group. Solriamfetol, Sunosi, is a dopamine and norepinephrine reuptake inhibitor, but it also has some agonistic properties at the trace amine-associated receptor and serotonin 1A receptors. Solriamfetol is approved by the FDA to treat excessive sleepiness in patients with obstructive sleep apnea, who were treated and still have sleepiness at doses that range from 37.5 to 150 milligrams. The purpose of this study was to begin to focus on the cognitive impairment in individuals with obstructive sleep apnea who had excessive daytime sleepiness. I'm going to share the results with you. The study design was a crossover design, which is a nice design because the patients sort of function as their own control. So it was a screening period to make sure patients were using the CPAP, they were adequately treated, they were not on concomitant medications that would distort the findings. They did have excessive sleepiness, and they did have some evidence of cognitive effect of the daytime sleepiness. After the screening period, there was a baseline period at which time the tests were performed, and I'll go over the tests in just a moment. But looking at sleepiness, objective measures of cognition, particularly memory and speed of processing, as well as subjective complaints of cognitive impairment. And the patients were randomized to placebo or solriamfetol, 75 milligrams for three days, and then 150 milligrams. Then at the end of two weeks, they were tested again. How, how sleepy are you? How objectively are you having in terms of executive function and subjective complaints as well? There was a one-week washout, and then the patients were then randomized to whatever, you know, placebo went to active compound, active compound went to placebo, again, blinded, and we repeated those tests. So let's look at what the results were. And as you can see, the individuals had baseline training as to how to do the tests and confirm protocol adherence and adequacy of CPAP. And then they were tested at two-hour intervals, 11:00 A.M., 1:00 P.M., 3:00 P.M., 5:00 P.M., which allows us to look at circadian processing in terms of executive function during that time. They also had the British Columbia Cognitive Complaints Inventory. And this really looks at, again, how well you're thinking, your recall, speed of processing, the impact on functionality, social interaction, family interaction. It looks at how, executive function impacts these individuals. There was a Patient Global Impression of Severity scale. Again, blinded. The patients told us, "How are you doing in terms of your executive function?" And of course, we had baseline and treatment measures, both placebo and active compound. "And how sleepy are you? What's your Epworth Sleepiness Scale score?" So we had an opportunity to look at these individuals. Of 173 participants screened, 59 were enrolled and 57 completed the study. And when you look at the individuals who were treated initially with solriamfetol or placebo and then crossed over, they had similar characteristics. The demographics were, individuals were in their early fifties. The female preponderance was about 33%. Remember, this is obstructive apnea, about 80% Caucasian, BMIs around 33. The point is that these individuals had similar characteristics at point of entry into the study, and of course, the recorded data, the digit symbol substitution test, which is our objective measure of cognition, the subjective measures, PGI and CPAP utilization or adherence, to these, to the CPAP therapy. So here are the study findings. The objective cognitive function test is a coding, coding test. It's a coding sub-test, and it's a variation of the digit symbol substitution test, which is a well-known test that's testing speed of processing and memory. And it is termed the Repeatable Battery for the Assessment of Neuropsychological Status. And when you look at individuals who are on placebo and then individuals who are on solriamfetol after the two weeks of treatment, there is a biological signal. It's statistically significant at the 0.009 level, which would show improvement in cognition in these individuals. The difference was 1.75, and the Cohen's d was about 0.4, which indicates that there's a signal here, biologically, that these individuals had improvement in cognition. When you looked across the day, two hours after therapy, four hours, six hours, eight hours, there is a signal that reached statistical significance at all of those time points, except at four hours. There was a trend, but it did not reach statistical significance within the confidence interval that we could say would separate from the placebo. But remember, the overall score there was, and at 2, 6, and 8 hours, it did reach statistical significance. That would indicate that there is an improvement in cognition in these sleepy individuals. When we looked at subjective cognition, this is used in the British Columbia Cognitive Complaints Inventory, we saw the same thing. When the score decreases, the patients are improved. And when you look at the solriamfetol group, 58 patients and 58 in the placebo group, you see a signal. The mean difference was 1.58, which is clinically relevant. The Cohen's d was 0.43, again, indicating that this is statistically significant and biologically relevant in terms of a signal that these individuals showed improvement in executive function. Importantly, when we look at safety, there were no unusual safety signals, especially when you go back and look at the pivotal trial data. But, any treatment adverse event in the solriamfetol group was about 19%. The placebo group was 10%, and as we might expect, we could see some nausea, anxiety, insomnia. Nasopharyngitis is very low and hard to interpret why that is. But the treatment adverse events were mild or moderate in severity, and there were no deaths, and, there were no treatment adverse events that led to discontinuation from the study. So I think we can conclude from this is, that when we take a population of individuals who are sleepy from obstructive sleep apnea, who are adequately treated with CPAP, they do have cognitive impairment, both subjective and objective measures, and as reported by Patient Global Impression of Severity. When we treat them with solriamfetol at a dose of 150 milligrams, initially 75 milligrams for 3 days, we could see, we could see a signal. There was both subjective and objective improvement in cognition and patient subjective symptoms. There was less sleepiness in those individuals as well. In addition, the adverse event profile was low. The drug was well-tolerated, and so out of this, we can interpret that solriamfetol certainly has the potential to improve cognitive function in patients with cognitive impairment associated with obstructive sleep apnea and excessive daytime sleepiness. Thank you for your attention. Thank you, Dr. Bogan. Our last speaker is Dr. Charles Czeisler, who is here to provide an overview of shift work disorder, or SWD. Dr. Czeisler, thank you for joining us today, and please go ahead. Greetings. My name is Charles Czeisler, and I'm the Frank Baldino Professor of Sleep Medicine at the Harvard Medical School and Chief of the Division of Sleep and Circadian Disorders at the Brigham and Women's Hospital. I'm going to be speaking about shift work disorder today, the diagnostic features, prevalence, adverse health outcomes, and approved treatments. Before I start, I just want to disclose a few things regarding my involvement in the development of the three FDA-approved treatments for circadian rhythm disorders. I led the registration trials for our both modafinil and armodafinil for shift work sleep-wake disorder. And I served as a consultant to Vanda Pharmaceuticals for the trial of tasimelteon for the treatment of non-24-hour sleep-wake disorders. I'm also a consultant to Axsome Therapeutics. Diagnostic features of shift work disorder are several. It can be insomnia during daytime sleep, or what I'm going to be focusing on today is excessive sleepiness during night work. By definition, this occurs when people are working a schedule that overlaps their usual sleep time, causing clinically significant distress or impairment for at least three months. Typically associated with either overnight shifts or early morning work shifts, starting, for example, between three and seven in the morning. It's distinguished from simply shift work because a fraction of people who work shifts, typically about a third of them, suffer much more than others and are clinically diagnosed with this condition. Problems with a shift work disorder is a bit hard to nail down. First of all, between 15%-30% of employed people in the United States work non-standard hours outside of the usual nine-to-five shifts. Many of those individuals have work hours that overlap with their usual sleep time. Then a subset of those individuals have shift work disorder. We looked at police officers in 2011, and published an article in JAMA, in which we specifically asked about whether they had excessive sleepiness using validated questionnaires at night or insomnia during their day work. We found that about 14.5% of those shift workers had both symptoms. About a third just had excessive sleepiness at night, and another, more than a third, had insomnia during their day sleep. If we looked at either/or, we found that more than half of the individuals had some type of symptom that would qualify them for shift work disorder. The bottom line is that of the 160 million, roughly, people who are employed in the United States, about 40 million work non-standard hours, and about 12 million of those may suffer from excessive sleepiness when working at night or on early morning shifts. Genetic background matters. About a third of people carry a genetic polymorphism, which makes them more vulnerable to working at night, such that they have, they're much sleepier when they work at night, and they have more adverse health complaints. They're not as well adapted to working at night when they do so, and that may make them more vulnerable to this condition. There are many adverse health outcomes associated with shift work disorder. Night work, in general, increases the risk of cardiovascular disease quite substantially. Of those working at night who have shift work disorder, they have an increased risk of accidents, absenteeism, depression, ulcers, poor sleep quality, subjective health complaints, and probably together with shift workers, have an increase in all-cause mortality, cardiovascular disease, diabetes, Alzheimer's disease, and dementia. So what to do? There are a number of management strategies for shift work disorder. The first is to try to shift the circadian phase of the individuals so that they're adapted to working at night. One can do that by increasing light exposure during the nighttime work hours and making sure that they sleep in darkness or giving them various chronobiotic agents. Another is to give them sleeping pills to help them sleep during the daytime. The third is to try to enhance their nighttime alertness, either with caffeine, light exposure, naps, or pharmaceutical agents. There have been some evidence reviews looking at the efficacy of non-pharmacologic interventions, and unfortunately, the evidence is very poor. The studies have been judged to be of low, very low to low quality, and the evidence derived from those studies was found to be weak. And so there are no non-pharmacologic interventions that have been proven to be effective in the real world, treating shift workers who have shift work disorder. Then when we come to pharmacologic treatments, only five randomized trials have ever been conducted of wake-promoting therapeutics to treat the excessive sleepiness associated with shift work disorder, and all have been done on two drugs, modafinil and armodafinil. I did two of those studies, or I led two of those studies. The one on modafinil and armodafinil both led to their being approved by the FDA for the treatment of shift work sleep disorder. However, post-authorization surveillance of adverse effects revealed 21 cases of severe skin reaction, of which 3 were fatal, and that led the European Medicines Agency to withdraw the approval for, of the license for the approval of, of modafinil for shift work disorder in 2011, and they never approved armodafinil for shift work disorder. The two treatments that have been approved differ, mainly associated with the half-life of the drug. So modafinil has a shorter half-life than armodafinil. As you can see from the data on the left, in the right-hand panel, at halfway through the shift, there's no difference between modafinil and placebo in the length of time that it falls to sleep-- that it takes to fall asleep if the individuals are scheduled to nap, which is a standard test for, called Multiple Sleep Latency Test, to evaluate as an objective measure of sleepiness. Armodafinil lasts throughout the shift, because it has a longer half-life, and the drug is taken before the shift starts. And that's shown on the right. Shift work disorder is simple to identify by primary care physicians, and in fact, a four-item questionnaire has been validated. It's shown to have an 89% positive predictive value for identifying people with shift work disorder. So you just ask four questions: Do you work non-standard shifts? Does it adversely affect your sense of well-being? Do you doze off while working, and do you doze off or fall asleep while driving home? If you answer those questions in a positive way, there's a nearly 90% chance that you have shift work disorder. Now, suvorexant has been shown, just as modafinil and armodafinil had been shown, to improve objective measures of sleepiness, in this case, as measured by the maintenance of wakefulness test after 12 weeks of treatment. And you can show, and as you can see here, as the dose increases from 37.5 milligrams to 300 milligrams, the improvement in the objective measure of sleepiness keeps getting better and better, going from 150 milligrams, a nearly 12-minute improvement in how long the individuals are able to stay awake to, at 300 milligrams, a 13.5-minute improvement. And not only are these objective measures improved, but also subjective measures of sleepiness are improved, as you can see from this slide, using the Epworth Sleepiness Scale. Again, a dose-related improvement so that people realize that they are less sleepy when they're working at night, when they're taking particularly 150 or 300 milligrams of suvorexant. The next slide shows that this improvement in the objective measures of sleepiness begins at week 1 and is maintained throughout the 12 weeks of treatment, in this time in patients with narcolepsy, although the data are very similar in patients with obstructive sleep apnea. You can see that again, there's a dose-response relationship and that the improvement is much greater than that seen in placebo, and it persists throughout the 12 weeks of the randomized clinical trial. The key takeaways are that shift work disorder affects about 12 million American workers. That patients with shift work disorder are at increased risk of error and accidents, including motor vehicle crashes and adverse health outcomes. That the evidence for the efficacy of commonly used non-pharmacologic interventions for the excessive sleepiness associated with shift work disorder is weak. Only two pharmacologic treatments have ever been approved by the FDA for shift work disorder, and the EMA, European Medicines Agency, withdrew its approval from modafinil after post-marketing severe skin reactions. Suvorexant is effective in treating excessive sleepiness in obstructive sleep apnea and narcolepsy, and those data support further exploration in shift work disorder. Thank you very much for your attention. Thank you. The lines will now be open for a brief question-and-answer session. Unfortunately, Dr. Czeisler won't be able to stay with us for this Q&A session, but Doctors McElroy and Bogan will be happy to address your questions. We'll take the questions in the order they were received, and as a reminder, questions can be asked through the call-in number. Our first question is coming from Joon Lee of Truist Securities. Please go ahead. Hi, thanks for taking our questions. You know, binge eating as a consequence of stopping GLP-1 therapy for weight loss was floated around at an obesity conference we attended a couple of months ago. Are you seeing any patients or heard of binge eating as a consequence of discontinuing GLP-1 therapy for weight loss? And if so, do you see any opportunity for suvorexant as sort of a maintenance therapy or bridge therapy as patients are titrated off of GLP-1 for weight loss? And I have a follow-up after that. Okay, well, thank you very much for your question. So I've been doing clinical trials in binge eating disorder for 30 years, and one of the reasons that I talk slowly about it and keep telling people it's a disorder is because so many people don't believe it exists. I have never seen. And I'm a psychiatrist, and I actually use a lot of GLP-1 agonists in my patients because I see, I treat patients who have psychiatric disorders and obesity, and I treat eating disorder patients. I have never seen use of a, you know, discontinuation of a GLP-1 result in de novo binge eating. Rather, we, our group uses the GLP-1 receptor agonist as treatment for those with binge eating disorder, refractory to all the standard treatment. Thank you. Thanks for the clarification. Okay. No. That's fascinating. So, it's really important to understand the obesity field and the eating disorder field. The obesity field, you know, just dwarfs just the eating disorder field. But eating disorders are probably, they're much, much, much more common than people realize, you know, and there's- Yeah, and I- This debate, is obesity an eating disorder? Well, I feel it is. So, anyway, well... So we have very strange thinking from both the obesity field and the eating disorder field on GLP-1. ... Excellent. Thanks for the clarification. And regarding the clinical trial design for shift work disorder, and this is more of a question for the management, but are you considering a placebo-controlled trial or an active controlled trial for, with one of the approved agents? Thank you. Hi, June. The studies will be placebo-controlled. Excellent. Thank you. The next question is coming from Joseph Thome of TD Cowen. Please go ahead. Hi there. Thank you for taking my questions. Maybe the first one, on binge eating disorder. Can you go into a little bit on just patient identification and diagnosis? I know you identified the distress involved in the patient, so I was wondering if that limits kind of self-presentation or if these patients are identified maybe through primary care physicians or other methods. And then second, is the sertraline placebo response generally consistent with what you would expect in a study, a little bit of, you know, over two days of a reduction? And is there a lot of variability in placebo response in these types of studies? Thank you. Okay. With binge eating disorder, let me answer the first, your second question first. You definitely get a placebo response in binge eating disorder. Absolutely. And our group basically has worked 30 years to figure out the trial methodology to determine whether a drug works in BED, and that's why we typically require... So one of the factors associated with placebo response is low severity. So less frequent binging is associated with a greater placebo response. So that in a standard BED trial, this is the trial we did, you know, we did this for Vyvanse to topiramate to sertraline. You know, we require people to have at least 3 binge eating days per week to come in. Because that's how DSM defines the disorder, we just, we can only measure efficacy by counting binge eating episodes. I'm sorry, what was the other question? The first one was just on patient identification. Do these patients self-identify, given, you know, the distress involved? I guess that maybe- That's actually an excellent question. No. So again, there, I try to stress this. There is an incredible lack of understanding of eating disorders in both the medical field and the public. No, these people don't identify themselves as that. And the Vyvanse trials and the sertraline trials, the vast majority of subjects had their BED diagnosed by the study personnel. So our group knows how to write an ad to get people to respond. And these people, they usually seek treatment for weight loss, and they've had numerous diets, tons of yo-yo dieting, and it's... Okay, and then the approval of Vyvanse really hasn't improved things very much because I think there's a stigma against treating people with obesity with stimulants. I'd like to call eating disorders the final frontier. I mean, the field, because I do a lot of work in mood disorders, too, so, and as well as eating disorders, and that when I compare the two fields, it's just mind-blowing how different they are. Eating disorders are just way, way, way behind the times. So. Perfect. I think they're much more common. Okay, they're much more common than our epidemiological data suggests, because we just don't have that much epidemiological data. And then people, like, obsess about these, you know, okay, did you one binge, two binge, three binge, you know, which it's so, binge eating is, there's no doubt in my mind it's much, much more common than our epidemiological studies suggest. Perfect. Thank you so much. Thank you. Thank you. The next question is coming from David Anselm of Piper Sandler. Please go ahead. Yeah, thanks. A question for Dr. McElroy on binge eating. So, you talked to the stigma of stimulant usage in obese patients. You also talked to the extent to which Vyvanse is efficacious. So I guess the question is, to the extent that, you know, you're not using Vyvanse, you know, what off-label uses of agents have you had real success? And then secondly, as you think about solriamfetol, what is the extent to which polypharmacy in these patients is going to play a role? Thank you. Okay. Thank you for the question. So I've been treating BED for 30 years, and so I've been using drugs off label for a really long time. I do, in fact, use a lot of Vyvanse, but as Dr. Cutler really nicely explained, it's becoming really, really hard for doctors to prescribe stimulants for their patients, even if it's like an FDA-approved treatment. And I have patients telling me they think they're, you know, being treated like criminals because they want a stimulant for their binge eating or ADD. So that-- I think that's an incredibly unfortunate complication of the opiate epidemic, because stimulants, in my experience, simply aren't abused like opiates. But, so, okay, other drugs I've used, basically drugs that affect the central nervous system that cause weight loss. So I've used a lot of topiramate. We were... I was involved in two studies of topiramate and binge eating. Again, highly effective, but not well tolerated. What I use now are the GLP-1s, and I've had nice luck with them, but I don't have any systematic data. The eating disorder field is extremely upset about GLP-1s. So, I'm really excited about solriamfetol. Our group is doing an investigator-initiated trial in solriamfetol, halfway through in BED. We have patients who say they really like the drug. It's just interesting. So, we're very positive about the use of solriamfetol in BED. Thank you. The next question is coming from Vikram Purohit of Morgan Stanley. Please go ahead. Hi. Good morning. Thanks for taking our questions. We had two, both for Dr. McElroy for binge eating disorder. And Dr. McElroy, apologies if you mentioned some of these considerations and we missed it. But first, for the two pharmacotherapies that you mentioned that are currently used and available and even some of the therapies you just mentioned that are used off-label, what level of annual duration do you see for patients that are using those options? And are patients using these treatments, taking them episodically or chronically throughout the year? And then secondly, assuming a new option like solriamfetol were to become available, how would you expect to begin using it for your patients? Is there like a specific segment of the population you'd be most focused on initially, or would you expect to use a new option broadly as soon as it's out there and it's available to you? Let me answer your, the second question, and then I'm gonna have to ask you again by your first. Okay, solriamfetol is Schedule IV as opposed to Schedule II like Vyvanse, so it's much easier for doctors to prescribe. It doesn't have the baggage of, of, you know, using a stimulant to treat obesity. So many people say BED is obesity. It's not. BED commonly co-occurs with obesity, but it's, it's much, much more than obesity. So I could see this drug being first line. I mean, we don't, you know... Okay, and then in terms of, other things we use off-label, and we use a lot of stuff. So the drug I use most commonly is topiramate. It is an anti-seizure medicine that is associated with substantial weight loss. It's part of the topiramate/phentermine combination, which was associated with the most weight loss of any drug until the GLP-1 receptor agonist came along. But the problem is, it's associated with a lot of cognitive impairment, and so it's not well tolerated. So I think the other thing that intrigues me about solriamfetol is its relatively benign side effect profile. Got it. And you mentioned that you wanted me to repeat the first question. The first question was on annual duration of use of current therapy. So, you know, for example, lisdexamfetamine. Vyvanse. Patients that are on that- Yeah. Yeah. So patients that are on that therapy, are they taking it episodically, kind of here and there as their condition lows throughout the year, or is it kind of something they're taking steady state? No, you take it every day. It's just like, just like treating depression. BED is more often chronic than not, and, you know, if somebody's got BED bad enough that they somehow make stumble into treatment, and you, you're lucky enough to find a treatment that works, it's like a lifetime treatment. They take it every day. Understood. And my final question here: so is compliance pretty good with this patient population for Vyvanse? Yes! Okay. Okay, one of the more fascinating things about eating disorders is how different people with BED are from people with anorexia or even bulimia. People with BED are incredibly distressed by their symptoms. They want help, and they often are incredibly compliant with treatment. Whereas with anorexia, you're, you know, dealing with people who don't want treatment. So, yeah. So yes, compliance is extremely good. Understood. Thank you. Thank you. The next question is coming from Charles Duncan of Cantor Fitzgerald. Please go ahead. Hi, this is Elaine on for Charles Duncan. Thank you for taking my questions. In the phase III, solriamfetol is being evaluated at higher doses than approved for OSA and narcolepsy. I saw that decreased appetite is highest at the 300 mg. And you mentioned previously, Dr. McElroy, that you perceive solriamfetol as having a benign side effect profile. But I'm curious whether insomnia could still be a potential side effect, or do you still think that the risk-reward profile is very much in favor of solriamfetol due to obesity and other complex requirements? That's an excellent question. In our investigator-initiated trial, where we can only go to 150, we are seeing insomnia. But it's interesting, patients, you know, they'll continue the drug because of the beneficial effects. So, no. So I think insomnia is going to be a side effect. I think it's probably something that can be managed, but we just don't know. But the thing about binge eating disorder and bulimia, actually, is you need higher doses. This is... Okay, not only are eating disorders not understood, but treating them is not understood. And the regulatory data that got approval for fluoxetine in bulimia nervosa showed a very clear dose-response relationship, where 60 milligrams was substantially better than 20, which was better than placebo. So with eating disorders, we know we have to give higher doses. You know, it's sort of like OCD, obsessive-compulsive disorder. You've got to give higher doses. So we think that those findings apply to binge eating disorder as well. In fact, let me just say this: if a drug reduces binge eating in either, in BED, it should also work in bulimia. If a drug works, reduces binge eating in bulimia, it should work in BED. Frankly, this compound... I am extremely excited about this compound, not just in BED, but in bulimia, which, okay, it's not as common, but it's harder to treat, so. That's intriguing. I also, I'm curious, is there a clinically meaningful reduction in the amount of binge eating, occurrences per week, or any reduction is good reduction? Are you talking about with solriamfetol? No, just with, yeah, with solriamfetol. We don't know yet. Okay? We don't know. We don't have data yet. So we have this very strong rationale to study it in BED, but we just don't know. But if it works in BED, there's going to be no doubt in my mind that it will work in bulimia. And, you know, like I said, the eating disorder field is in the Middle Ages. They're behind every other field in psychiatry. They're very anti-psychopharmacology, even though it's clear most people with an eating disorder end up on medication. It's just bizarre, frankly, because I've been doing this work for 30 years. It would be wonderful if we had a drug that worked for, that was approved for BED and bulimia, because there is some diagnostic overlap. There's quite a bit of diagnostic overlap. Understood. Thank you for your insight. Yeah, this is Richard Bogan. I'll jump in a little bit because in the open-label extension trial for sleep apnea and narcolepsy patients, I believe 60% of the patients, when clinicians adjusted the dose on the open label, were on 300 milligrams. So we have some pretty good efficacy and safety data on that particular dosing. Yeah, yeah. And, uh- And I- And quite frankly, the prevalence of insomnia was fairly low. Now, these are sleepy people, not not normal bulimic people, but are- Mm-hmm. Eating disorder people. But, but again, and of course, the duration of action, the half-life of it is sort of typically we see a biological signal about nine hours. So, sometimes the insomnia is relatively, I mean, typically the insomnia is relatively infrequent, and that may be different in a different population. That's interesting. Thank you for taking our questions. Thank you. We're showing time for two additional questioners. Our next question is coming from Richard Flynn of Mizuho. Please go ahead. Richard, please make sure your phone's not on mute. Oh, sorry. Thanks. This is Richard on for Graig Suvannavejhh. So I have a couple questions. One question is for management, and that question is, how are you prioritizing these clinical trials, and how should we think about the cost of these studies for, you know, 2024 and beyond? And then, for Dr. McElroy, you mentioned that solriamfetol could be first line for BED. Ultimately, how many patients do you think have BED that are treated for BED? And then how many patients would you use solriamfetol in the end? Thanks. Sure. With regards to the question for management, so we are expeditiously developing these additional indications. As we discussed in the opening remarks, we'll be initiating the additional phase III trials in the first quarter. So that's the priority. And then, with regards to the spend, these have all already been budgeted for. So, you know, we've been working obviously on these indications with the FDA for a while. We're now talking about them. Okay, let me start, and then you can ask questions to get clarification. I'm sorry, I don't know numbers, but BED is ridiculously common. Our best epidemiologic data, which is not great, suggests 3% of the population in the United States has it. And that's actually using much more rigid criteria than the DSM-5 criteria. So I'm convinced that it's much more common than our epidemiologic data indicates. Now, how many people get diagnosed? I think that's actually just really, really, really low. So you could look at Shire's experience. I thought Shire did—Well, first of all, the studies were, I thought, incredibly well done, ridiculously positive. But there was, and they did, I thought, a very good education program on BED, but it didn't take off. I think doctors were afraid to prescribe a stimulant to people with binge eating because they see the obesity more than the binge eating. So with solriamfetol, if it's got, I'm hoping, similar efficacy, but it's Schedule IV, I think doctors will feel much more comfortable prescribing it. It doesn't have the baggage. So amphetamines had this baggage of being abused in obesity, which I'll remember. I was on the phone with The New York Times, and they drilled me for a half hour, and the article they wrote had nothing to do with binge eating. It was all about, you know, Shire just got a drug, a stimulant approved for obesity. So there's just, there is this stigma, baggage, whatever, where, where I don't think solriamfetol would have that because it's Schedule IV. But, but you're, you, if, if you're gonna market it for BED, there's going to have to be an educational program because it's, like I said, it's bizarre how people don't understand how you can, you can lose control of gambling, you know, sex, alcohol, but, and you can but you can also, they don't understand that you can lose control over your eating, so. Thank you. The next and final question is coming from Myles Minter of William Blair. Please go ahead. Thank you, Megan. I'm just wondering what proportion of patients are actually obstructive sleep apnea or excessive daytime sleepiness. I'm just intrigued at the comment that you made that pretty much all drugs that have worked in the latter, you know, have shown interesting data in BED if they are a DNRI. And the sertraline trial that you showed us in that trial that also had background OSA or, or narcoleptic-like symptoms. Thanks very much. I'm sorry, who's the question? Okay, go ahead. It was kind of breaking up. I'm not sure who it was directed to or- Yeah, no. Okay, go ahead. Because I couldn't tell, all right. I couldn't quite tell either. Hey, Miles. I guess. Go ahead. Yeah, I don't know. I didn't hear the whole question. Yeah. I don't know who it was directed to. Okay, Miles, could you ask again? It broke up just a little bit, please. Yep, no problem. So I'm just wondering what the proportion of patients are that have disorders. What are comorbid with obstructive sleep apnea or excessive daytime sleepiness? That's the first part. Part was in the sertraline trial, showed us substantial amount of patients that were comorbid with those indications, just given the comments you made, that drugs of a DNRI mechanism that have shown promising data in narcolepsy do tend to show amazing data in B. Thank you. I'm sorry, I still missed a lot of the question. Yeah, I think I'm sort of getting it. Sorry about that connection. I think I'm sort of getting the gist of it. This is Richard Bogan. Good. Okay. I think that patients who are sleepy have executive function abnormality, they're also hungry. And so those are, those are sort of what we consider to be primal signals, and of course, the neural network is very individual, but those do overlap. But I think if you're sort of saying, "Oh, wait, we're really treating sleep apnea patients or narcolepsy patients with these particular drugs," I would say no. What we do know is that patients with sleep apnea and narcolepsy do have comorbid depression. They also have comorbid attention deficit disorder, which I think is kind of an overlap in the- Mm-hmm. the neural processes that cause dysfunction. So when we're looking for a biological signal from a drug, if I'm understanding your question, it's not because we're treating another disorder. I think it's that we are enhancing these alerting pathways, which in turn improves executive function, cognition, feeding, you know, all of those are... And even mood, might be, incidentally, helped. So I think when we think about target medicine and we're, affecting different neurotransmitters, then that's the way I would approach it, not, I, I was actually treating another disorder. Makes sense. That answered it. Thank you. Thank you. That concludes our question and answer session. I will now turn the floor back over to Axsome's CEO, Dr. Herriot Tabuteau. Please go ahead, sir. Thank you all for joining us on today's solriamfetol Investor Day event. As you've heard throughout this morning's presentation, the pharmacology of solriamfetol has significant potential to address multiple unmet medical needs. If successfully developed, the addressable patient populations would support blockbuster potential. There are a number of value-driving milestones upcoming for solriamfetol, including three planned phase III trial initiations in the first quarter of 2024, followed by data from the focused phase III trial in adults with ADHD. I would like to especially thank our physician experts, Doctors Chepke, Cutler, McElroy, Bogan, and Czeisler, for their participation. I hope everyone has a great day. Ladies and gentlemen, thank you for your participation. This concludes today's event. You may disconnect your lines or log off the webcast at this time, and enjoy the rest of your day.