Good morning, and welcome to the Axsome Therapeutics conference call. I would now like to turn the call over to your host, Mark Jacobson, Chief Operating Officer at Axsome Therapeutics. Mark, please go ahead.
Thank you, operator. Good morning, and thank you all for joining us on today's 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, commercial plans, 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 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, Nick Pizzie, Chief Financial Officer, Lori Englebert, Executive Vice President of Commercial and Business Development, and Dr. Amanda Jones, Senior Vice President of Clinical Development, as well as our distinguished guests who will be introduced by Dr. Tabuteau. After the presentation, we will open the line for questions, and questions will be taken in the order they are received. With that, I will turn the call over to Herriot.
Thank you, Mark. Good morning, everyone, and welcome to the Sunosi investor update. We signed the agreement to acquire Sunosi on March twenty-eighth. Since the closing of the U.S. portion of the acquisition on May ninth, Sunosi has been rapidly integrated into Axsome's industry-leading neuroscience portfolio and our excitement for the product has only grown. Sunosi is the first and only dual-acting dopamine and norepinephrine reuptake inhibitor, or DNRI, approved for excessive daytime sleepiness, or EDS, due to narcolepsy or obstructive sleep apnea, or OSA. Sunosi has a differentiated clinical profile based on strong efficacy in the approved indications as well as a well-established safety profile. We are excited about Sunosi not only because of its potential for significant growth in EDS and narcolepsy and OSA, but also for its potential in new neuroscience indications.
Today, we are announcing our plan to develop Sunosi for the treatment of attention deficit hyperactivity disorder, or ADHD. The pharmacology of solriamfetol may be particularly suited to treat this distressing condition, which affects approximately 12 million Americans. We intend to rapidly develop Sunosi for ADHD and plans are underway to initiate a phase III trial in this indication this year. We are honored to have with us today three distinguished physicians, scientists, and key opinion leaders who will provide clinical overviews of EDS in narcolepsy, of EDS and OSA, and of ADHD. Joining us today are Dr. Richard Bogan, Dr. Andrew Krystal, and Dr. Stephen Faraone. 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 EDS associated with narcolepsy. Dr.
Krystal is the Ray and Dagmar Dolby Distinguished Professor of Psychiatry and Neurology at UCSF Weill Institute for Neurosciences and Vice Chair for Research in the Department of Psychiatry. Dr. Krystal will provide an overview of EDS in obstructive sleep apnea. Dr. Faraone is the Distinguished Professor in the Department of Psychiatry and Neuroscience and Physiology at SUNY Upstate Medical University and Vice Chair of Research in the Department of Psychiatry. Dr. Faraone will provide an overview of ADHD. Following the KOL presentations, Amanda Jones, Axsome's Senior Vice President of Clinical Development, will discuss the ongoing and planned clinical development of Sunosi. We will then open it up for questions to our physicians and scientific experts.
Following the Q&A, Lori Englebert, Axsome's Executive Vice President of Commercial and Business Development, and Nick Pizzie, Axsome's Chief Financial Officer, will provide a Sunosi commercial overview and financial update. We will then open it up to questions for the Axsome presenters. A key part of the rationale for the acquisition of Sunosi is the excellent strategic fit with our AXS-05 product candidate for the treatment of major depressive disorder and our AXS-07 product candidate for the acute treatment of migraine. This strategic fit is based on the overlap of prescriber base and disease comorbidities. I will provide a brief regulatory update on AXS-05 and AXS-07 before turning it over to our first KOL presenter. The NDA for AXS-05 for the treatment of MDD is currently under review. On Friday, we received from the FDA proposed product labeling for AXS-05.
We are reviewing proposed labeling and will reply to the FDA to secure final labeling agreement. As a reminder, we also received from FDA the postmarketing requirements and commitments for this NDA, and we have started to honor those. With regards to AXS-07, our NDA for this product candidate in migraine, we previously announced the receipt of a complete response letter for this NDA. We have been actively working to prepare for a Type A meeting to discuss our planned resubmission and expect that meeting to occur in the next couple of months. That completes the regulatory update. It is now my pleasure to turn the floor over to Dr. Richard Bogan to discuss excessive daytime sleepiness in narcolepsy. Dr. Bogan, thank you for joining us today. Please go ahead.
I am Dr. Richard Bogan. I am a pulmonary, critical care physician who practices sleep medicine in South Carolina, have clinical employment and also see patients, and we do clinical research here in our laboratory. I'm here today to talk to you about narcolepsy. Narcolepsy is a disorder that is characterized by excessive daytime sleepiness. The peak incidence actually is in the teenage years. We make the diagnosis in young adults, but it can occur at any time. These individuals have profound daytime sleepiness despite an adequate opportunity to sleep. We believe that this disorder is associated with orexin signaling abnormalities, certainly type one narcolepsy. We have type one and type two, which I will explain, but these individuals have abnormality of orexin signaling, presumptively due to an autoimmune abnormality. They got the flu, and it injured the orexin cells.
An orexin is an important neuropeptide that downstream stimulates other regions in the brain. In this diagram, you'll see the norepinephrine, but also dopamine and histamine, acetylcholine, serotonin. These neurotransmitters are very important for regional activation of the brain and stabilization of wakefulness. In the absence of orexin, state instability occurs. These individuals have trouble staying awake, despite the fact that they had adequate quantity of sleep. In addition, the sleep centers, which are normally inhibited during the day, and the dreaming centers are disinhibited, so these individuals have episodes of getting sleepy if they're relatively inactive. They also tend to have what we call REM dissociative symptoms. They tend to have very vivid dreams. They tend to have episodes of sleep paralysis. The reason for that is when we are dreaming, we're paralyzed.
These individuals may be falling asleep or waking up and feel briefly paralyzed and, as I said, vivid dreams. They may actually see or hear the dream. We call those hypnopompic or hypnagogic hallucinations. Obviously can be unsettling. Many of the patients have unsettled or irregular sleep patterns, multiple awakenings in the night. Sometimes that can be confusing because they interpret the sleepiness in the daytime due to the disrupted nocturnal sleep. Of course, cataplexy is the ultimate REM dissociative symptom. If you think about being awake and something triggers the dreaming generator while you're awake, the brain's already awake, but there's downward inhibition of motor activity, a paralysis. These individuals with strong emotion can have episodes of muscle weakness, so they can just melt into the floor and or knees buckling or the head gets heavy, or they consider themselves clumsy.
This is certainly Type 1 narcolepsy. We're not really quite sure about Type 2. Some individuals think there is maybe a deficiency or a mild deficiency, or there may be some orexin signaling abnormality, but we're not really sure. They have very similar symptoms as in Type 1 narcolepsy in that they are tired and sleepy and have these REM dissociative symptoms. The vivid dreams, paralysis, hallucinations commonly occur in these individuals, but they don't have cataplexy, so that's Type 2. The prevalence of narcolepsy, we think, is about 1 in 2,000. As I said, the peak incidence is around age 15, 16, but they oftentimes go 10 years before we make the diagnosis because they don't know how sleepy they are, and they don't know that these REM dissociative symptoms are abnormal.
They say, "It's just me." It's a very prevalent disorder, and unfortunately, most of the patients have not been diagnosed. We've probably only diagnosed about 50% of them, but these patients do present to us. When you begin to explore the prevalence of these symptoms, you see excessive sleepiness is 100% cataplexy. About 70% of patients, disrupted nocturnal sleep is very prevalent. Not all patients have the REM dissociative symptoms of hallucinations or paralysis that occurs. The paralysis is interesting because sometimes it can be mistaken for panic attacks or even sleep apnea because these individuals wake up, and they can't move, so they panic, and they feel as if they can't catch their breath. Let's move on to treatments. What do we do to treat these individuals?
They come to us and they say, "Doc, I'm tired, I'm sleepy, I can't think, I can't remember. I sometimes do things, I don't remember doing them." We call it automatic activity. "I constantly need to nap." Or I desired a nap, or in certain situations where I'm trying to stay awake, I have trouble staying awake. That can obviously affect workplace performance, even driving and social interaction. It has a huge impact on quality of life. The excessive sleepiness, as I said, is 100%. The medications that we use traditionally are Solriamfetol, our newest addition to the FDA-approved meds. Solriamfetol actually works on those dopamine and norepinephrine receptors. It is a reuptake inhibitor, so it's increasing exposure of the neurons to dopamine and norepinephrine, which helps people stay awake. Old drugs, Modafinil and Armodafinil.
Armodafinil has just the one isomer that Modafinil has in it, and that's primarily, we believe, through dopamine reuptake. Of course, we use the classic stimulants, the drugs that are used in attention deficit disorder, methylphenidate and amphetamine. There is a histamine-mediated drug, Pitolisant, which is also commercially known as Wakix. Pitolisant has been beneficial in both the sleepiness as well as the cataplexy. Of course, Oxybate and Oxybate now is in two flavors, sodium Oxybate and then the lower sodium Oxybate Xywav, which has 92% less sodium. What about the cataplexy? Well, what I said earlier is that orexin and of course downstream norepinephrine and serotonin, those inhibit the REM generator. We've actually used drugs that will sort of augment the signaling to try to prevent the REM generator from causing muscle paralysis in the daytime.
We've used off-label antidepressants, anticholinergics, serotonin reuptake inhibitors, or selective norepinephrine reuptake inhibitors have also been used. The drugs that have been approved are oxybate, sodium oxybate, and the lower sodium oxybate has shown a usefulness both in the excessive sleepiness but also the cataplexy. Pitolisant, again, working through histamine, can improve excessive sleepiness, but also has been shown to help with the cataplexy. Of course, Pitolisant was primarily studied in Europe. Now let's think about the guidelines. The American Academy of Sleep Medicine has actually published, reviewed the scientific information that's out there on these medications, looked at the randomized controlled trials, looked at the study design, and examined the efficacy and side effect profile, quite frankly, of these various medications. We're talking about Solriamfetol. Solriamfetol is listed as a strong recommendation for treating patients with narcolepsy.
It has demonstrated both efficacy and safety in narcolepsy patients, so much so that the American Academy strongly recommended this as an option for therapy in our patients. Let's move on and look at the actual data, the science behind Sunosi solriamfetol in treating excessive daytime sleepiness in narcolepsy patients. One of the parameters that we use when we do research is the maintenance of wakefulness test. If you think about state stability, the normal human is awake in the day and sleep at night. Their orexin works, their dopamine, norepinephrine, all of those work in the daytime. They can stay awake, and then at night those turn off and the person sleeps, and they cycle in an ultradian rhythm. Every 90 minutes, they have these periods of non-REM and REM sleep as they cycle through the night.
Of course, narcolepsy patients, those are disrupted because of the REM dissociative symptoms. One of the measures that we use is the maintenance of wakefulness test. Here we're isolating a patient or a research subject, dark room, lights out, and have them sit up and try to stay awake. Now, these are sleepy people, and so we measure them at times across the day. How well can their brain stay awake when they're trying to stay awake? We do this at two-hour intervals, so two, four, six. We could do them at one hour and three hours, five hours. We do it across the day as an objective measure of the ability to remain awake. Typically, if I were to do that to you would probably be in the dark room 40 minutes.
You would probably be north of 20 minutes. We take the average across the whole day. Siesta time, you might fall asleep, but I would expect you, if you're normal, to be well over 20 minutes. These folks were typically right around 12 minutes or so. Actually shorter than that, less than 10 minutes for narcolepsy. That was really more the sleep apnea, sleepy people. We gave them placebo. We gave them Solriamfetol 75 milligrams, and we gave them Solriamfetol 150 milligrams. Double blind, placebo-controlled, randomized, so the patients didn't know, the investigators didn't know. When we did the nap studies across the day, you can see the MWT improved. It improved 4.7 minutes, which is a big signal, quite frankly. 4.7 minutes with 75 milligrams, 9.8 minutes with 150 milligram.
We call this effect size. This is one of the biggest effect sizes we've seen in any research group. Now, we can't compare different studies and different cohorts at different times, but these were pretty big signals that these individuals were better able to remain awake. The other question we ask is, does it work for a long period of time? Do we see tolerance? You can see the data in the graph, which looks at the sleep latency over time, and you can see it one week all the way out to 12 weeks. If you look at the MWT across that entire time, you can see it separates from the placebo group. The 75 milligrams showed a signal. The 150 milligrams showed a bigger signal in terms of the individual's ability to remain awake. What about across the day?
Let's look at the MWT across the day. The other question is, okay, how quickly does it work? Can we see a signal within an hour? Does the signal last across the entire day? Because we all know siesta time, we all tend to get drowsy in the middle of the afternoon. What does this drug do? Does it tail off or not? When you look at the placebo group, it's really interesting to look at the placebo individuals in terms of their baseline and the change in the placebo group. You can see that little dip at trial number four, seven hours, the siesta time.
We can get a placebo effect, but importantly, at 75 milligrams and at 150 milligrams, you can see at one hour and out to nine hours a statistically significant change in individuals compared to the placebo group and compared to their baseline in terms of efficacy and the ability to remain awake. This is objective evidence of duration of therapy. We didn't see tolerance and also improvement across the day for the entire nine-hour period of time. Now let's look at the Epworth Sleepiness Scale score. The Epworth Sleepiness Scale score is a standard way for us to talk about sleepiness. It's, you know, eight items, 0 to 3. How likely are you to doze off under these circumstances while sitting and reading, watching TV, while you're driving, stopped at a traffic light, et cetera? Typically, you're gonna be less than 10 or less.
I'm a six on my Epworth score. Patients with narcolepsy, particularly untreated, their Epworth score is up around 18, 17, 16. I mean, they are very sleepy individuals, and they will tell you anytime they're quiet or inactive, they tend to doze off. What did we see in the Epworth Score subjective measure? This is a validated clinical tool that we use in research a lot. How sleepy are you, narcolepsy patient, when I give you placebo compared to baseline, Solriamfetol 75 and 150 milligrams, and you see a signal. At 75 on the left-hand side. In the gold, you see a 3.8 signal, and in the lavender color, 150 milligram, we saw a 5-point signal. Now we think clinically meaningful change in the Epworth score is right around 2.5-3.
You can see these are meaningful to the patient in terms of a biological signal that says that they are less sleepy. Did we see duration over the 12-week period of time? Did we see tolerance? When you look at that graph on the right, at week one all the way out to week 12, you can see the signal separates from the placebo group. This is the change from baseline at week one all the way out to week 12. We saw a signal, remember, at one hour for the MWT, and we saw a signal as far as the Epworth at one week all the way out to 12 weeks, again demonstrating efficacy. Of course, the American Academy of Sleep Medicine and the FDA use this data to try to determine efficacy and safety.
Speaking of safety, on this slide, you can see the adverse events. Obviously, when we do a clinical trial, we capture every adverse event that occurs, whether it's related to the drug or not. One of the ways that we look at this is side effects that occurred in over 5% of people, and it was greater than the placebo group. This is pretty much what we expect when we use medications that activate the neurons in the brain and excite them to keep an individual awake. We may actually see some other CNS side effects. We could see headache or nausea. We could see a change in appetite. We could see insomnia, obviously, if the drug kept someone awake too long, and anxiety. You can see that the prevalence of these disorders is fairly low.
I mean, it's typically less than 10%. There was a dose-response relationship. You saw some headache in the Solriamfetol group at 14% and then again, you can see that drop off. This is a listing of all the side effects that occurred both in the placebo group as well as the Solriamfetol 75 and 150 milligrams. I usually tell my patients, you know, headache, dizzy, nausea, could cause some anxiety. I rarely see insomnia in my narcolepsy patients, but it's possible that we could see that in someone and maybe have to make dose adjustments or something to that effect. I'm gonna show you another study. Now, this study actually was a long-term study looking again at efficacy going out 40 weeks, so this gives us some idea.
The study design is in such a way that it allows us to look at tolerance and rebound and withdrawal symptoms in these individuals. As you can see, this actually was a group of individuals with obstructive sleep apnea, which I'm not gonna talk about, but there are patients with obstructive apnea who are still sleepy and also narcolepsy patients. Look at their Epworth scores. You can see 17, 15. These individuals are sleepy enough, and again, with sleepiness, you have problems with executive function, speed of processing, motivation, mood, all of those are affected. These individuals don't feel good. When you look at them on drug over a period of time, you can see that there is a reduction in the Epworth score at two weeks, 14, 27, 40 weeks that does show clinical relevance over a long period of time.
Again, we interpret this as not much evidence of tolerance. As you know, in the Schedule II drugs, tolerance is an issue. People on methylphenidate and amphetamines can develop tolerance and ask for dose escalation, and we can begin to get more into safety issues in terms of the effect on sympathetic tone in those individuals. This is a nice piece of data looking at the Epworth score over a long period of time. Now, how does this translate into what we do? This is a nice little study from Germany. Actually, the Europeans have a registry in Germany, France, Italy. They track patients, and this is a retrospective observational study. You always have to be careful with these kinds of studies, but it's asking what are we doing in the clinic? This actually relates to the German study.
They took a group of individuals and said, "Okay, I'm treating your narcolepsy. You're still sleepy. This is what I did." In these individuals, they had to take the Solriamfetol for at least six weeks. You can see the strategies behind this. Some of the patients changed over from a current wakefulness promoting medication, most likely Modafinil or methylphenidate. You can see they were changed over to Solriamfetol. There's a signal. There's again about that 4-point change in the changeover. Some of them actually was an add-on. We don't have data, obviously, from the randomized controlled trial of adding on, but this is what they did in the clinic. 19 patients, they added on, again, a 3.7-point improvement in the Epworth score. The patients told them, "I'm less sleepy." You had naive patients.
They came in newly diagnosed narcolepsy. What you see is a 6.1 improvement. When you put them all together, there is about a 4.3 improvement. Again, clinically relevant. We think 2.5, maybe 3 is what is clinically meaningful to the patient in terms of the effect on, of sleepiness, in terms of quality of life. This is a nice real-world study. Again, what do we do with this drug in our clinics? Obviously coming from Germany. With that, I will close and look forward to any questions. I think the important message here is narcolepsy patients have pretty profound daytime sleepiness, and the sleepiness impacts quality of life and their ability to remain vigilant. Now we have multiple options for therapy in terms of wakefulness-promoting medications.
You saw the American Academy of Sleep Medicine in terms of their recommendations, and you had a chance to look at both efficacy and safety data. Thank you for your attention.
Thank you, Dr. Bogan. I will now turn it over to Dr. Andrew Krystal to discuss excessive daytime sleepiness in obstructive sleep apnea. Dr. Krystal is the Ray and Dagmar Dolby Distinguished Professor in the Departments of Psychiatry and Neurology and Vice Chair for Research in the Department of Psychiatry at UCSF Weill Institute for Neurosciences. Dr. Krystal, thank you for joining us today, and please go ahead.
I'm Andrew Krystal. I'm Professor of Psychiatry at the University of California, San Francisco. I'm gonna give a brief overview of excessive daytime sleepiness in obstructive sleep apnea. Obstructive sleep apnea is a common disorder that affects people, occurs in the form of repeated collapses of the upper airway during sleep that are often associated with drops in oxygen level, and it also is associated with disturbed sleep in terms of fragmentation and people not feeling restored. The typical symptoms include being sleepy during the day, snoring, noted apnea events, and people having the experience of waking with difficulty breathing and gasping for air. This is a condition associated with a very high rate of morbidity and mortality. Among the adverse health consequences are hypertension, diabetes, associated coronary artery disease, depression, and daytime accidents.
The standard therapy for this condition is to use a device that blows air through the upper airway during sleep to keep it open, basically as a splint to prevent the collapses. This is called CPAP or continuous positive airway pressure. It comes in some forms that are often commonly used called BiPAP, which is where the pressure is varied during inhalation and exhalation, and then APAP, which is auto-titrating CPAP. Unfortunately for many people, the sleepiness that's associated with obstructive sleep apnea continues to be present despite the use of this standard therapy for the condition. One of the challenges is that many people have difficulty tolerating the CPAP. They have real issues and challenges in using it every night or throughout the entire night.
Many people stop using it over time, or they use it for only a part of the night or some nights. There are several wake-promoting agents that are FDA-approved for treating the excessive daytime sleepiness that occurs in adequately treated patients for obstructive sleep apnea. This includes solriamfetol, modafinil and armodafinil. There are also some medications like dexedrine. These are classic stimulants that are used off-label for treatment of the residual sleepiness in obstructive sleep apnea. Excessive daytime sleepiness occurring in people with obstructive sleep apnea is extremely common. It's seen in roughly 87% of people as measured by the standard tests we use, or one of the standard tests we use for assessing daytime sleepiness objectively in the laboratory and multiple sleep latency test, multiple nap tests.
Among those people, many of them suffer from residual excessive daytime sleepiness despite using the standard of care, CPAP. Across studies, it's reported to be 34%-65% of. Of the general population, it's 9%-22%. It's really unclear why this excessive daytime sleepiness persists despite use of continuous positive airway pressure in those who use it 100% of nights all night long. One reason that we do see this is that many people don't use it a 100% of nights all night long because it's difficult to do, and some people just take it off without even being aware of it in the middle of the night. That's one of the contributors. This obstructive sleep apnea-associated daytime sleepiness has significant impacts on people's lives and on the public.
There's a 2-3 times increased risk for motor vehicle accidents, 80% increase of risk for work-related accidents, and decreased work productivity, high prevalence of depression, anxiety. In general, people suffer from impairments in many key functions: attention, memory, and executive functions that are critical to many of the functions people engage in during the day. In terms of numbers, it's estimated that about 12 million people have excessive daytime sleepiness and obstructive sleep apnea. About 5 million use CPAP. Of these, those who continue to have significant sleepiness are estimated to be about 2.7 million, despite using CPAP. There's an estimated nearly 1 million people who use wake-promoting agents or stimulants in this context.
Important point from my point of view as a psychiatrist and sleep medicine expert is that these people who have residual daytime sleepiness and OSA are prone to having significant depression. Just in general, people who have excessive daytime sleepiness who have obstructive sleep apnea have a rate of depression of 62%. That's like six times the general population prevalence of depression. If you look at meta-analyses that have tried to evaluate how commonly depression patients have obstructive sleep apnea, it's like 36% ballpark. That's around double to triple the general population prevalence of apnea in those without depression.
One of the reasons that it's believed that the depression is so common in people with obstructive sleep apnea is that there is overlap in the symptoms. There are common factors in the two disorders. For example, the fatigue and loss of energy, poor concentration, being slowed down, having weight gain are all symptoms of both of these conditions. It's not surprising that there are elevated rates of co-occurrence of these two things. I think while the American Psychiatric Association has recommended assessing people with all psychiatric disorders for obstructive sleep apnea because it's elevated in a number, not just depression. It's also specifically made recommendations in evaluating and treating people with depression.
I have to say, by and large, these guidelines are not followed super closely because of the underdiagnosis or lack of training of many psychiatrists, but this is increasing. There's a lot of these efforts for educating psychiatrists and new data coming out showing that the presence of obstructive sleep apnea is limiting the antidepressant response, are increasingly having impacts on psychiatric care. Now, I'll quickly review some data from the solriamfetol clinical trials that are relevant to this key question that we're focusing on of the relationship of obstructive sleep apnea and depression. First, there's strong evidence that solriamfetol improves excessive daytime sleepiness in people who have obstructive sleep apnea, as it does in people with narcolepsy.
The clinical trials data show that very clearly, and there's an increase in the therapeutic effect with increasing dose and statistically significant effects are found on the two major outcomes that were used in the clinical trials compared with placebo. This is the Epworth Sleepiness Scale and the Maintenance of Wakefulness Test, where people are given an opportunity to sleep during the day multiple times, and they're asked to try to stay awake in a dark room in bed while it's quiet. The more specific result that's relevant to what we're talking about is that we did an analysis comparing whether there was an effect of solriamfetol compared with placebo on these parameters in people who had a history of depression versus those who didn't.
Given that there's so many people who have depression and who have obstructive sleep apnea associated with sleepiness, it's likely that this medication will be used in those with depression. There's a number of reasons that it could not be the case. For example, brain circuitry is different in those with depression than those who are not. You know, people are taking medications that might interact with the effects of Solriamfetol, might interfere with them. We're very interested in sort of assessing whether or not a therapeutic effect was present in people with depression and as well as those without.
The data sets that were available had allowed us to do an analysis of those who had a history of depression, some of whom had current depression, but also some of whom who have had it only just in the past as a proxy for trying to look at this question. We found that the therapeutic effects of the drug were present, whether or not people had a history of depression, both on the Epworth Sleepiness Scale and on the Maintenance of Wakefulness Test. Similarly, people who were currently using antidepressants while they were in the trials also had just as strong a therapeutic effect on the Epworth Sleepiness Scale and on the Maintenance of Wakefulness Test compared to those who didn't.
Again, that's a critical issue for knowing whether there's likely to be any therapeutic effects in people who have depression, who essentially all of which or nearly all of which will be taking antidepressants. It's clear that this didn't impede the therapeutic effect. We also looked to see, does this increase the risks of side effects? Looking at the data for solriamfetol in those who have a history of depression and no history of depression suggests that this is not the case. We looked not only at those with obstructive sleep apnea who were treated with solriamfetol, but also people with narcolepsy.
Just because the numbers of people in the history of depression group, and it gets relatively small when you cut the pie up into more pieces by looking at that. It's consistent across, you know, the OSA and narcolepsy data that there isn't any clear consistent increase in adverse effects compared with placebo when you look across both conditions. Overall, just wanted to summarize that obstructive sleep apnea is a very common condition, and it's treated with a therapy as a standard first-line intervention called continuous positive airway pressure. Despite using that, many people with obstructive sleep apnea continue to experience excessive daytime sleepiness, and solriamfetol is an agent that shows clear therapeutic effects for that excessive daytime sleepiness.
Depression is very common in people who have obstructive sleep apnea and particularly those who have residual excessive daytime sleepiness. It turns out that solriamfetol has potent therapeutic effects in that sleepiness whether or not you have a history of depression or whether or not you're taking antidepressant medications and without increasing side effects, suggesting that it would be a very effective treatment for the many people with excessive daytime sleepiness, especially with apnea, who have major depression.
Thank you, Dr. Krystal. I will now turn it over to Dr. Stephen Faraone, who will provide an overview of attention-deficit hyperactivity disorder. Dr. Faraone is the Distinguished Professor in the Departments of Psychiatry and Neuroscience and Physiology at SUNY Upstate Medical University and Vice Chair for research in the Department of Psychiatry. Dr. Faraone, thank you for joining us today, and please go ahead.
Hi, I'm Stephen Faraone. Today I'm talking to you about an overview of attention-deficit hyperactivity disorder, or ADHD. I've been studying ADHD for over 30 years now, and I first wanna tell you that the evidence base for ADHD is huge. In 2021, with a group of international colleagues, I published the International Consensus Statement on ADHD. You can take a look at that at adhdevidence.org to find more backup for the information I present to you today and lots more information about the disorder. Let's start with the question: Well, what is ADHD? To be diagnosed with ADHD according to the American Psychiatric Association, the patient must exhibit developmentally inappropriate levels of hyperactive impulses and inattentive symptoms for at least six months. These symptoms, there must be six or more symptoms for children, five or more symptoms for adults. Importantly, the symptoms must occur in different settings.
ADHD is a pervasive condition. It doesn't only occur in the home or in school or in the workplace. Some symptoms and impairments must be present prior to age 12, and these symptoms must cause impairments in living. Importantly, it must be the case that no other condition or disorder better explains these symptoms than the diagnosis of ADHD. The symptoms of ADHD change across the lifespan. In this slide, you can see how symptoms from childhood through adolescence and adulthood tend to change from young kids being very hyperactive, impulsive, I mean, they're running around, climbing on furniture, blurting out answers in school. Through adolescence and adulthood, the symptoms of hyperactivity and impulsivity attenuate. We don't find adults, for example, climbing on furniture, and they're replaced by inner sense of restlessness, misjudging time, making impulsive decisions, and importantly, emotional dysregulation.
Because the symptoms change over time, sometimes ADHD in adults is not recognized, and that's a problem that many of us are trying to change to improve the care of adults with ADHD. ADHD is sometimes considered to be a mild condition. That is wrong. There is a serious real-world impact of ADHD on patients that has now been shown through multiple studies from around the world. All of these outcomes here, accidental injuries, bone fractures, traumatic brain injury, criminality, drug and alcohol abuse, cigarette smoking, educational underachievement, sexually transmitted infections, depression, suicide, teenage pregnancy. All these outcomes we see in ADHD children as they move into adolescence and into adulthood, especially if they are not treated for the disorder. One of the more important findings that occurred in the 1990s and beyond was that ADHD tended not to occur by itself.
It tended to be associated with other conditions. It is an early signal that the child is at risk for other problems. All of the ones listed here on this slide have now been replicated by numerous laboratories and clinics around the world. Mood disorders, anxiety disorders, autism spectrum disorders, antisocial disorders, eating disorders, and most worrisome to parents, substance use disorders. Importantly, their presence does not rule out the diagnosis of ADHD. Another important feature of ADHD is that it is a common disorder. We know now from many, many studies that the prevalence of ADHD is about 6% in kids and about 3% in adults. If you apply those figures to the population of the United States, we're talking about 4.3 million youth with the disorder and 7.2 million adults.
Contrary to some media reports, the prevalence of ADHD has not changed over the past three decades. Moreover, there are no significant differences in prevalence between North America and Europe, Asia, Africa, South America and Oceania. We now have a very huge evidence base for epidemiologic studies of the disorder. We've learned a lot about the causes and pathophysiology of ADHD. In the cause perspective, we now know that ADHD is caused by the confluence of many, many genetic risks and many, many environmental risk factors. Most of these environmental risk factors occur very early in life and affect the fetus, such as pregnancy and delivery complications. This confluence of genes and environment impairs brain systems that are involved in the executive control of attention and behavior. We refer to these as the frontostriatal and frontoparietal networks.
These are involved in what we call goal-directed executive processes that help the individual regulate their attention and regulate their behavior and regulate their emotions. Particular underactivation of these systems leads to impaired control of the limbic system, which controls the emotional symptoms that we see in ADHD. There are parts of the frontal cortex of the brain we call orbital frontal cortex. They're connected to an area called the ventral striatum, which is involved in the control of reward. Because of this, people with ADHD have poor control over rewards. What that means is they don't respond to reward and punishment the same as the average person. This is one reason we believe they're at higher risk for substance use disorders, because that area of the brain also regulates the use of substances.
Underactivation of that part of the brain leads to poor control of attention to stimuli that should be important in the environment. That means that the child sitting in the classroom, instead of paying attention to the relevant stimulus, which is the teacher, they're paying attention to something they see outside the window. It's also been documented now over the years that the medications that are therapeutic for ADHD work in the brain networks that are implicated in ADHD. These are primarily noradrenergic networks and dopaminergic networks. Let's talk a bit about current treatments for ADHD. You can see here on the right, this is a treatment algorithm for ADHD. Essentially, clinician starts out thinking or asking the question, does the patient have a comorbid condition? Is it more severe than the ADHD? If it is, they treat the comorbid condition.
If a patient's suicidal, you treat their depression, not their ADHD. Otherwise, you treat their ADHD, and you go down the right-hand of the algorithm. Then you ask, are there contraindications for the use of stimulants or personal preference against stimulants? If there are not, you go down the stimulant side of the tree to the right. If there are, you go down the non-stimulant side of the tree. This algorithm is based on treatment guidelines from the American Academy of Pediatrics and other guideline organizations. As you can see, the stimulants are amphetamine and methylphenidate. There are three types, short-acting, intermediate-acting, and long-acting. The non-stimulants we have now, alpha-adrenergic medications, clonidine and guanfacine, atomoxetine, and actually a new one after this algorithm was written in 2015, which is extended-release viloxazine, just came out last year.
Essentially, when any medication is used, you monitor progress. You either get full response, partial response, or no response at all. Depending upon the outcome, the prescriber may switch to another medication or may add a non-pharmacologic treatment. Importantly, there is a 50% discontinuation rate after 6 months for most medications of ADHD, which leads to low response rates. Here you see the medications approved by the FDA for ADHD. Importantly, there are two types of stimulants we mentioned. The immediate-release formulations and the extended-release formulations can be found for both methylphenidate and amphetamine. This gives prescribers a range of duration between 4-16 hours. Liquid and chewable forms are available. Stimulants are all reuptake inhibitors of the dopamine transporter, and they also, amphetamines typically release monoamines as well.
In contrast to the stimulants, the non-stimulants work primarily in noradrenergic systems. Although there's a new non-stimulant, extended-release viloxazine, which also is a dopamine transporter reuptake inhibitor, possibly works in the serotonergic system as well. We mentioned two alpha-2 agonists, guanfacine and clonidine, which work in that noradrenergic system I showed you in the slide earlier. We know from many, many randomized controlled trials that the stimulant medications are somewhat more efficacious than the non-stimulant medications. You can see here in this figure from a book chapter I wrote, 2014, essentially, we're measuring efficacy by the effect size or the standardized mean difference, where larger is better. There's only one non-pharmacologic treatment that's shown any evidence for being useful in ADHD, and that happens to be the use of omega-3 fatty acids.
As you can see, the effect size is about 0.2 or less, which means it's not very effective at all. All these other non-pharmacologic treatments that have been tried for ADHD, unfortunately, don't work on their own. This is why medications are considered to be the first-line treatment for ADHD by most professional organizations. What are the unmet needs in psychopharmacology of ADHD? Well, let's start with the stimulants. Stimulants are very effective, but unfortunately, they're Schedule II controlled substances. That leads to headaches with prescribing, having patients have to come in more frequently than they would otherwise to renew prescriptions. It's really headaches all around. Some practitioners don't want to get involved with a controlled substance because they're worried about getting in trouble with the Drug Enforcement Administration at some point.
Because the stimulants, although when used therapeutically, they are not addictive and in fact will prevent substance use disorders, they are at risk for being misused, abused, and diverted. This is a fairly large problem among adolescents and young adults, especially in the college population. There are also some irritability and rebound phenomena that makes stimulants difficult to use and adhere to, and what my pediatrician once called loss of sparkle, which is the many patients tend to lose the sense of spontaneity and joie de vivre that they had in their life. It's a main cause for not adherence or moving to another medication. On the other hand, the non-stimulants don't have these problems, but they tend to have lower effect sizes. The difference is even bigger for adults than it is for children.
Clonidine and guanfacine have sedation, especially at higher doses, and lack of data or much data in adults with ADHD. Atomoxetine, which has been around for quite a long time, now has a black box for suicidality by the FDA, and it does cause nausea in many patients when titrated ineffectively. That leads to a lot of non-compliance and failure to tolerate the medication. All medications for ADHD have this non-adherence problem I mentioned, and none of them are very good at treating emotional dysregulation or executive dysfunction. For example, the effect of stimulants on a scale of 0 to 1 is about nine. The effect on emotional dysregulation, executive dysfunction is about a three. For non-stimulants, it's about a 1.5.
More work is needed to come up with medications that do a better job treating those areas. Let me summarize what I've said to you today. Number one, ADHD is a common impairing disorder in both children and adults. ADHD is caused by the confluence of many genetic and environmental risk factors. There's no one single cause of ADHD. Pathophysiologic studies of ADHD implicate dopaminergic and noradrenergic circuits in the brain. Many treatments are available, but many unmet needs exist. If you would like to see more curated information about ADHD, go to www.adhdevidence.org, which is my website. Thank you very much.
Thank you, Dr. Faraone. We will now turn it over to Amanda Jones, Axsome's Senior Vice President of Clinical Development and Medical Affairs, who will discuss our ongoing and planned clinical development programs for Solriamfetol. Amanda.
Good morning. I'm Amanda Jones, Senior Vice President of Clinical Development, and I'm excited to discuss the ongoing and planned clinical development programs for solriamfetol. Today, I will review the planned clinical development for solriamfetol in ADHD and discuss the ongoing SHARP study, which is evaluating the effects of solriamfetol on cognitive impairment. Lastly, I will quickly highlight some of the ongoing investigator-initiated trials with solriamfetol. One of the main reasons we were excited about the opportunity to acquire solriamfetol was for the potential to develop it for additional CNS indications, specifically ADHD. As reviewed by Dr. Faraone, dopaminergic and noradrenergic pathways are implicated in the pathophysiology of ADHD. The pharmacology of solriamfetol, a selective dopamine and norepinephrine reuptake inhibitor, therefore align nicely with the brain networks implicated in ADHD. Solriamfetol is a non-stimulant with a low abuse potential.
It's dosed once daily and has a well-established safety and tolerability profile. These are key features which make solriamfetol have an attractive product profile for ADHD. We are making preparations to submit an IND, enabling us to initiate a phase III study in adult patients with ADHD later this year. Our current timelines project potential top-line data in the H2 of 2023. We will provide a more definitive timeline once we announce the study initiation. Following completion of the adult ADHD study, we would intend to initiate pediatric ADHD studies to support an FDA filing. The planned clinical trial for adult patients with ADHD will be a randomized, double-blind, placebo-controlled, four-week study evaluating the effects of solriamfetol on ADHD. The primary endpoint will be the change in the AISRS, or Adult ADHD Investigator Symptom Rating Scale, at week 4.
Eligible patients will be adults aged 18-55 with a primary diagnosis of ADHD using the DSM-V criteria and confirmed via the clinician-administered adult ADHD clinical diagnostic scale. We look forward to sharing additional details of this study when we announce the trial initiation. Transitioning to evaluation of Sunosi's potential effect on cognition in patients with EDS and OSA. OSA and EDS in OSA are associated with impairments in attention, memory, and executive functions. About 40% of OSA patients complain of cognitive difficulties. These cognitive difficulties are one of the top symptoms that have an impact on patients' daily activities. The decrease in cognitive function in patients with OSA impacts work performance and social functioning and increases the risk for occupational and motor vehicle accidents.
In the SHARP study, we are evaluating the impact of solriamfetol on cognitive outcome measures in patients with EDS associated with OSA and impaired cognitive function. The SHARP study is a randomized, double-blind, placebo-controlled, multi-center, two-week crossover study evaluating the effects of solriamfetol on cognition in patients with EDS and OSA. Eligible patients are randomized in a 1-to-1 fashion to one of two sequences, either solriamfetol followed by placebo or placebo followed by solriamfetol. During each period, the dose is titrated over three days from 75 milligrams to 150 milligrams per day. The two periods are separated by a one-week washout. The primary endpoint is the change from baseline to week two in the DSST, or Digit Symbol Substitution Test. Key eligibility criteria include adults aged 18 to 65 years who have OSA and EDS with impaired cognitive function.
The study is currently ongoing, with top-line data anticipated in the Q3 of 2022. The pharmacology of solriamfetol is potentially relevant to multiple CNS conditions. Currently, 12 investigator-sponsored studies are ongoing. Seven of these are interventional clinical trials evaluating solriamfetol in a variety of indications, including binge eating disorder, ADHD, shift work disorder, chronic fatigue syndrome, post-stroke wakefulness, insomnia, and fatigue associated with MS. We look forward to the investigators' completion of these trials and the subsequent data presentations. In summary, the pharmacology of solriamfetol is relevant to multiple new potential indications. Upcoming clinical development milestones for solriamfetol include top-line data from the SHARP study expected in the Q3 and initiation of a phase III adult ADHD study in the Q4 of this year.
Thank you, Amanda. So with that we will now start the Q&A session, whereby we will have our physician and scientific experts who will be available for questions with regards to their presentations. I'll turn it over to Mark, who will lead the session.
Great. Given the webcast format, if you do have questions, you know, feel free to submit those online, and then what we will do is read those back. We'll re-read who the question is from and then turn it over to our guests on the call. Subsequent to the next phase of the presentation, we'll open the line for further Q&A. Okay. The first question we have is from Joe Thome at Cowen, and it is: How are you incorporating Sunosi in narcolepsy the most, first line versus additive or switch? And is this the first branded agent that you reach for following any associated step-through that's applicable?
This is Ric Bogan here. I would say that Sunosi, to me, has an advantage. One, the effect size was impressive, though again, we don't have comparative studies. I'd have to caution that, but it is renally excreted, which means that we don't deal with the hepatic enzyme difficulty. Modafinil, armodafinil activates the cytochrome system in the liver, which affects birth control. Females who are on steroidal birth control, we don't use modafinil or armodafinil or pitolisant in narcolepsy patients because of it decreases the effectiveness. The advantage of solriamfetol, Sunosi, is that it's renally excreted, so we don't really worry about that. It is a first-line drug. It's right up there with modafinil or armodafinil. In select patients, those are the ones that we consider as first-line therapy.
Great. Next question coming from Charles Duncan at Cantor, and: What line of therapy do you prescribe Sunosi for N1 versus N2 and why? Narcolepsy 1 and 2 for the folks on the phone.
Yeah. It's indicated for both patients because both of them have excessive sleepiness, and solriamfetol, Sunosi, is effective in both type one and type two narcolepsy. I'm pretty much equivalent. Type one narcolepsy patients we think tend to be a little bit sleepier. As you saw from the German study, oftentimes we need polypharmacy in those individuals. It's not unusual to have patients on oxybate and solriamfetol. They're not mutually exclusive. Yeah. I'll tell you the answer to the question is, we use it in both type one and type two.
Great. Thank you. Follow-up question from Charles at Cantor is specifically for Dr. Krystal. Does the use of antidepressants reduce OSA EDS symptom burden? More importantly, would you have any concerns with prescribing Sunosi to a patient that is on stable antidepressant medications?
Thanks for the question. I don't have any concerns about using Sunosi in people who are on stable antidepressant medication. It is. You know, I think the data we have show that it is clearly safe and can work in people on taking antidepressant medications. Of course, the size of the groups on any specific antidepressant aren't big enough to be able to determine effect sizes or side effects for each drug. In general, that's true. In my clinical experience, I use it in people who are taking antidepressants and have not had any problems. It's actually kind of a nice strategy in some ways because the pharmacology of it is a kind of a reasonable augmentation strategy for antidepressants for people who don't respond well to them.
The norepinephrine and dopamine reuptake inhibition is one of the established sort of paths we tend to tap into for treatment of depression in general. It's a very good strategy, and I use it clinically relatively frequently.
Thank you. A question from Sarah Schram at William Blair. Do patients using SSRIs for depression have a differential response to Sunosi for OSA in your experience?
They don't. They seem to do about as well. Again, there's overlap in the mechanism of some of the established antidepressants like bupropion. It has norepinephrine and dopamine reuptake inhibition properties. It is not as potent a wake-promoting agent as Sunosi, but there again, it's a reasonably good strategy, and I use it frequently without any difficulty, and the data support that.
Great. Thank you. Follow-up from Sarah. Any concerns over increased heart rate or blood pressure signal with Sunosi? Are there a significant amount of narcolepsy or OSA patients that have cardiovascular comorbidities that an alternative agent would be better suited for?
Ric Bogan here. Anything that wakes you up can have the potential to increase in sympathetic tone and heart rate and blood pressure. We monitor our patients, and as a rule, the majority of patients do fine. We don't see a heart rate and blood pressure signal. It is dose response related and individual related and comorbidity related. Narcolepsy patients observationally do have a higher prevalence of cardiovascular disease and hypertension. You know, their own stimulants, and those also increase heart rate and blood pressure. We monitor our patients, but as a rule, that's it. It's not a big impediment, at least in our narcolepsy patients. I'll leave it to Andrew Krystal to talk about the sleep apnea.
Yeah. I mean, cardiovascular disease is very common in people with obstructive sleep apnea. You know, I think that the data from the clinical trials with obstructive sleep apnea speaks for itself, that the rate of problems with hypertension and elevated heart rate is not notable. It's not significant in that group. People tolerate it quite well. As Dr. Bogan mentioned, it's something you always wanna monitor in anybody you're treating with an agent that has the potential to enhance heart rate or blood pressure, which this drug does by mechanism. It's just not, doesn't arise hardly at all in clinical use, nor again, was it evident in the trials.
Thank you. Question from Bert Hazlett at BTIG. Are there any differences in prescribing practices between adolescent or adult patients with ADHD? I'm not sure if there's any commentary there for Dr. Faraone.
No, there really aren't any differences. The one main difference might be that adolescents are, of course, at higher risk for substance use disorders. In that case, stimulant medications are frequently avoided. Otherwise, it would mainly be a dose-dosing issue. Adolescents sometimes need higher doses because of body weight.
Thank you. I'm going over to Joon Lee at Truist. What differentiates Sunosi from modafinil or armodafinil, you know, the efficacy or safety, and how would you go about choosing among myriad available drugs for EDS?
I'll start. Modafinil, Armodafinil mechanism of action, we believe, is dopamine reuptake. They are effective, and clinical studies have shown effectiveness for excessive sleepiness, the Epworth score, compared to baseline with about a three. Again, we can't compare cohorts, different studies. Remember, the effect size of solriamfetol in narcolepsy patients was, you know, a large effect size. We consider Modafinil, Armodafinil and Sunosi sort of equivalent in terms of, you know, top line, first line therapy, based on efficacy and safety. Now, the big differential is Modafinil, Armodafinil, as I said earlier, is metabolized through the liver, and it activates some of the CYP enzymes which affect birth control, but Sunosi does not, being renally excreted, so it's a little bit easier to use, in terms of drug-drug interaction. Hope I answered the question.
Yeah, they're effective drugs and patients have individual response. We may have a patient respond to one and not the other one for some reason. Remembering Sunosi is dopamine and norepinephrine reuptake inhibition.
Thank you. A follow-up from Joon. How prevalent is depression among patients with EDS? Would you treat MDD comorbidities with EDS with both antidepressant and Sunosi or just treat EDS and hope for a resolution of MDD?
Andrew Krystal, I can address that. I think the standard of care would be to use an antidepressant and a wake-promoting drug like Sunosi. But I would be cognizant of mechanism. I would generally not add to bupropion, you know, first I would treat a person with bupropion, and then I would use Sunosi or afterwards with that if it was inadequate wake promoting effect of the bupropion or, you know, other serotonin-norepinephrine reuptake inhibiting antidepressants, and then, you know, cautiously add on Sunosi afterwards. The rate of daytime sleepiness in depression is actually reasonably high.
It's particularly common in people with bipolar depression and seasonal affective disorders that have seasonal changes in their mood, which is probably about 10%-20% of people with depression. It's extremely common. There's, you know, debate in the sleep medicine world about, you know, how should we think about this? Is it a form of what we should call idiopathic hypersomnia? I think the reality is functionally it's treated by generally adding antidepressant therapy and adding a stimulant medication, but it doesn't have sort of a separate designation as a disorder of excessive sleepiness unless it occurs in the setting of something like narcolepsy or apnea or some problem of that sort. Hope that answers the question.
Thank you. Two questions from Jason Gerberry at Bank of America. First one for Dr. Faraone. Based on what you know about Sunosi, can you offer any hypothesis as to why you'd expect the drug to clinically differentiate versus existing stimulant treatment options, and whether those theoretical improvements address an unmet need?
Okay. A tough question, but I'll do my best. So, you know, the current landscape, you've got stimulants on the one hand and the non-stimulants on the other hand. Sunosi, I'm hoping, will fall kind of in between, because we know that the drugs that are most effective have strong dopaminergic activity, which is why the stimulants are Schedule II, because they can be addictive. Sunosi is, I believe, Schedule IV. The other non-stimulants are not scheduled drugs. I'm hoping that Sunosi has a strong dopaminergic effect, enough to do well in ADHD symptoms also fairly quickly. Because, well, I shouldn't say remember, you'll notice the non-stimulants typically take around 6-8 weeks to work, whereas the stimulants, you can see an effect in two weeks. They take about four weeks to have the full effect.
Sunosi might also work more quickly. That's my hope for it, but I will have to see what the trials show.
Thank you. A follow-up here is a general question. Can you speak to the impact COVID-19 might have had on Sunosi adoption?
I'm sorry. Could you repeat that question?
Oh, yeah. Sure, I think this is open to anyone that would like to address it.
Yeah.
A complementary question. Can you speak to the impact COVID-19 might have had on Sunosi adoption?
Yeah, I don't think it's had any effect on the adoption of Sunosi. Obviously, there's interest in long COVID and chronic fatigue, but I don't really know of any, you know, where we stand on that at the moment. We do think of narcolepsy patients having an autoimmune response to infection, influenza, and common cold, mono, and the body's immune system mobilizes and injures the orexin cells. Of course, in the pandemic, von Economo's encephalitis taught us a lot about sleepiness because those people in the early 1900s, some of them developed insomnia and some of them developed hypersomnia, narcolepsy from encephalitis from the pandemic. I think the story is not fully in yet in terms of what COVID might do in terms of brain function.
There are others probably have better expertise than I, but it's from a Sunosi perspective, other than access to care and volume, I don't see any story there.
I will say, Andrew, that you know, there's a fair number of people who have suffered from COVID, who are described as long haulers, who have chronic symptoms. A number of those people suffer from significant fatigue and there can be a sleepiness component to it, and there's really no great consensus on how to best address it. Wake-promoting medications are being considered and sometimes being used functionally and you know, on a practical basis to try to help these people. I think some wake-promoting agent use has increased in that setting, but by and large, my sense is it hasn't affected the process.
You know, that reminds me, Dr. Krystal, the Modafinil and Armodafinil actually was studied for fatigue back in the day, you know, shortly after they were released, and fatigue of cancer therapy. I think you saw the investigator-initiated trials is, you know, MS fatigue is, Modafinil, Armodafinil have been recommended for MS fatigue as well, and obviously shift work. There are a lot of potential options here, and the story is not in, and it'll be interesting to see how those investigator-initiated trials will help in terms of, approaching fatigue itself as well as sleepiness.
Agreed.
Thank you. A second question from Joe at Cowen. For OSA, do you need to have demonstrated failure of CPAP in order to progress to pharmaceutical intervention?
Yeah. Great question. The way that the studies are done, so as to prevent failure to adequately treat obstructive sleep apnea, is that we identify people who are using CPAP at the rate required by Medicare to meet adherence criteria. It's you know, at least four hours a night for 70% of nights or more. This is those people then are the sort of standard cohort included in the studies and if they have daytime sleepiness. Some of those people are using CPAP 100% of the time, as I mentioned, and yet they have sleepiness and there are complex reasons why that may be, which we don't fully understand.
There's some people for whom that use is maybe not fully addressing the problem because they're sleeping seven hours and they're using it for, let's say, four and a half. Some of their night is being spent unaddressed with unaddressed sleep apnea. That's the standard of care and the model that's been used. I'd say in clinical practice, it's a much more practical set of things that go into this decision. If a person is significantly sleepy and you've made your best effort to have them adhere to CPAP, they don't quite meet that criteria, and they're able to keep their device because often companies will take their CPAP devices if they aren't remaining adherent.
By and large, any residual sleepiness in a person who's using CPAP to their best ability and with the best help you can give them is considered for wake-promoting therapy.
Yeah. Dr. Krystal, I might add, in the, obviously, solriamfetol, Sunosi does not treat obstructive sleep apnea. It helps with the sleepiness. In the trial, the FDA and the sponsor actually included patients who weren't wearing CPAP. The main reason for doing that was to look at efficacy and safety in that subgroup to see if there was a signal. Interestingly, there was a signal that the sleepiness did improve, and the safety profile was the same in people who aren't using their CPAP as much as they should. Now, you don't translate that into, okay, it's okay to just use solriamfetol in patients with obstructive sleep apnea. I mean, we know they're at medical risk, and we should. As, Dr.
Krystal said, "In the clinical practice, we look at patients both from a morbidity, mortality perspective, but also their symptoms and what can we do to alleviate those particular problems. I thought that safety and efficacy data was kind of interesting to include that cohort.
Yes, very interesting. Thank you for adding it.
Thank you. There are a significant number of questions this morning. We will try and get through a few more for our guests this morning, and then we'll continue with the remainder of the presentation, which is a commercial and financial update. A few more questions here for the physician and scientific experts. First one from Matthew Kaplan at Ladenburg Thalmann for Dr. Faraone. How would you potentially incorporate Sunosi in the treatment paradigm for ADHD?
Well, you know, it would be ideal if Sunosi comes close to having an effect size as good as the stimulant medications. It could be a first-line treatment for ADHD. Currently, the first-line treatments are the stimulant medications. Non-stimulants are second line. As I said before, Sunosi may kind of fall in between. The closer it creeps up to having similar effect size, even if it's a little bit less with similar tolerability, then it would do very well. I mean, you know, modafinil was never approved by the FDA for ADHD, but in studies in children, it's nearly as effective as methylphenidate and has essentially the same tolerability as methylphenidate. I do think there's hope that Sunosi will kind of reach that point of good effect size, good tolerability, and could be a first-line agent.
Thank you. Going to David Hong at SMBC, you know, what proportion of ADHD patients are generally treated with stimulants versus non-stimulants? And do most ADHD patients on non-stimulants usually end up switching to stimulants over time?
Typical response rate to stimulants is around 80% or so. Same thing for the second stimulant. Most of the people with ADHD are going to be on a stimulant medication. I don't have the actual figures for you, but it's at least gonna be 70%/30%, if not 80%/20% stimulant/non-stimulant. Some patients on non-stimulants will, if they start on a non-stimulant, the current non-stimulants, many of them will switch to a stimulant medication because the non-stimulants are just less effective.
Thank you. For final question here, before we switch back over to the or continue with the remainder of the presentation. Do the majority of treatment emergent adverse events subside with repeat dosing over time, or do they randomly occur with each dose? Do you become tolerized to therapy over time?
Yeah. Narcolepsy, I think, symptoms tend to occur early. We'll know right away if the patient is tolerant of the medication. Again, sort of, headache and nausea, some anxiety are the most common. But if we start at a lower dose and kind of work our way up, sometimes the, you know, the side effects are mild. The patients, if they're mild, they do adapt. We rarely see. Once the patient's on stable dosing, it's unusual to see the emergence of new side effects unless some comorbidity develops or, you know, you add some concomitant meds that for some reason might augment it, but it's uncommon. Once we get through that initial titration, the patients rarely develops kind of random side effects.
Would agree.
Well, that was the last question that we'll take in the interest of time for this session. We'd like to thank Dr. Bogan, Dr. Krystal, and Dr. Faraone for the discussion. We will now turn it over to Lori Englebert, Axsome's EVP of Commercial and Business Development, who will provide a Sunosi commercial update. Lori.
Thank you, Herriot. Good morning, everyone. The U.S. portion of the Sunosi acquisition from Jazz Pharmaceuticals was completed on May ninth, and I am happy to report that the transition was seamless with no disruption to patients. We are extremely proud of the efforts made by the team in such a short amount of time to achieve this significant milestone for Axsome. At the time of completing the acquisition, Axsome conveyed approximately 75 employees from Jazz, of which the majority were sales reps. Immediately upon closing the acquisition, sales reps were trained and back in the field promoting within just two days. Axsome's digital-centric commercialization platform is key to our commercial strategy for Sunosi and will allow our sales reps to engage more efficiently and effectively with HCP targets. As a note, the EU portion of the close is scheduled to be later in the H2 of the year.
The opportunity for growth remains substantial for the current indication in both indicated patient populations. As a reminder, Sunosi is indicated for excessive daytime sleepiness, or EDS, in individuals with narcolepsy or with obstructive sleep apnea, or OSA. Narcolepsy is an orphan condition that affects approximately 185,000 people in the U.S., all of whom experience EDS. Narcolepsy is largely undiagnosed, but once diagnosed, has extremely high treatment rates, with more than 95% of diagnosed patients being drug-treated. OSA, on the other hand, is a highly prevalent condition that affects an estimated 22 million US adults. It is estimated that up to 87% of OSA patients experience EDS, and even after continuous positive airway pressure or CPAP use, EDS can persist in up to 65% of patients. OSA is a severely undertreated condition with only 6% of diagnosed patients being drug-treated.
Sunosi is the first and only DNRI approved for EDS and narcolepsy and OSA. Sunosi offers a differentiated profile with strong efficacy, a well-established safety and tolerability profile, high patient-reported improvement, and extremely high prescriber satisfaction. When polled, 99% of HCPs who have used Sunosi stated that they would recommend the product to a colleague. Currently, Sunosi has broad access with over 96% of commercial lives covered and a robust patient support program that includes prior authorization support and co-pay assistance. During the transition period, weekly prescriptions were maintained at pre-acquisition levels, and I am excited to announce that in the last reportable week, the product reached an all-time high for TRx. As a reminder, Sunosi launched in the U.S. in July 2019. The initial growth trajectory was negatively impacted by pandemic restrictions, which were enforced within six months of launch.
Despite this headwind, script growth continues to trend upwards. The growth potential for Sunosi is significant. Currently, Sunosi has only a 2% patient share for drug-treated OSA patients and a 7% patient share for drug-treated narcolepsy patients. With the current very low penetration rates, strong product profile, and broad payer coverage, there is substantial room to significantly grow Sunosi adoption and revenue. As discussed by Dr. Krystal, a majority of patients with EDS and OSA also experience major depression. Consistent with this comorbidity, a substantial portion of treated OSA patients are seen by psychiatrists. Among specialists, psychiatrists overwhelmingly treat the most patients, prescribing pharmacotherapy to 66% of patients who are treated by specialists.
Psychiatrists are also familiar with identifying and treating excessive daytime sleepiness as over 40% of OSA patients who are seen by a psychiatrist are drug-treated for EDS, compared to just 3% for PCPs. Psychiatrists are a key prescribing group for Sunosi, and a potential overlap with our AXS-05 targets will allow for a highly complementary sales targeting effort once AXS-05 launches. We are excited about the significant potential growth opportunities with Sunosi and have taken a very strategic approach to commercialization. Since deal close, we have focused the field force on high-potential prescribers. High-potential prescribers are HCPs with a large pool of diagnosed patients, have high script volume, and are familiar with wake-promoting agents.
To successfully drive market share with these high-potential prescribers, we have aligned our territories, focused our sales force, and will utilize DCC to optimize HCP engagements. The potential near-term launch of AXS-05 for major depressive disorder, if approved, will enable us to leverage synergies with our psychiatry sales efforts. We also see a real need and opportunity to educate HCPs and patients on identifying and treating EDS in OSA or narcolepsy. We remain excited about this high potential product and look forward to sharing our progress with you in the future. I will now turn it over to Nick, who will go over financial performance, growth opportunities, and provide a financial update.
Thank you, Lori. I'll now give a brief overview of Sunosi historical and potential revenue, along with some additional financial guidance as it relates specifically to Sunosi. Sales for Sunosi have continued to grow year- over- year. 2021 net sales grew 105% versus 2020. For the most recent full quarter, Q1 net sales for Sunosi were approximately $16 million, an increase of 37% from the same quarter in 2021. Peak sales for Sunosi for EDS in narcolepsy and OSA have the potential to be in the $300-$500 million range. We hope to grow Sunosi in these indications by increasing our market share in OSA and narcolepsy. Additionally, we intend to focus on disease awareness with the HCPs and patients with the goal of increasing OSA treatment rates over time.
As stated earlier, the ADHD market is very large and continues to grow. With approximately 100 million annual ADHD scripts dispensed in the U.S. alone, each 1% share would be equivalent to roughly $900 million in gross sales. We are very excited about the potential of Sunosi in the ADHD market and plan to start our first pivotal trial later this year. Sunosi has high clinical and commercial potential based on the following. One, it's well established and clinically meaningful efficacy in EDS associated with narcolepsy and OSA. Two, it's consistent positive feedback from HCPs, patients, and providers. Three, patents extending out to 2040. Four, its potential in other neuroscience indications such as ADHD. Based on current and potential future indications, we believe that potential peak net sales for Sunosi could be $1 billion or greater.
As a reminder, the WAC for a 30-day supply of Sunosi is $755 for either the 75- or 150-mg tablets. With the U.S. portion of the transaction closing on May ninth, Axsome began recording sales immediately thereafter. Based on our current assumptions, we expect gross-to-net for Sunosi to be approximately 50%. Upon closing of the U.S. portion of the transaction, title to Sunosi-related inventory transferred to Axsome. We estimate that gross margin on Sunosi net sales is expected to be in the mid- to upper-70s percent. Along with the cost of the product, royalties to Jazz, SK Biopharmaceuticals, and Aerial BioPharma are also included in the cost of goods sold.
We expect a small loss for the U.S. Sunosi operations for the remainder of 2022 as we transition and implement Sunosi into Axsome's infrastructure. This loss includes the further development of Sunosi for the ADHD indication, along with supporting the post-marketing requirements while investing in all aspects of commercialization. The intellectual property for Sunosi acquired from Jazz was domiciled outside the U.S. and remains outside of the U.S., resulting in a favorable tax jurisdiction. Additionally, NOLs that Axsome has accumulated may be used to further enhance profitability. I will now turn the call back over to Mark to lead the Q&A discussion.
Great. We'll pause a minute here just to collate some questions and then we will take the same approach and read back the questions that have been received and respond. There are a few that would go to Lori with respect to the commercial activities and approach. I'll group them together. They are iterations of the same fundamental question. What can the company do to drive further identification of patients with EDS associated with OSA and greater rates of treatment in this population? A similar question is what is Axsome doing to adjust the dynamic with targeting and prescriptions?
Yeah, great. I'll take that in two separate questions. One for consumers and patients. You know, as mentioned before, we do have in place the exact same patient support programs that Jazz had in place. Extremely robust patient support efforts to make sure that patients who get on product are able to stay on product without being financially implicated. You know, in terms of driving the market growth with patients, that is you know, a marketing tactics that we are constantly exploring and pressure testing. We will deploy very targeted media to patients to help drive them. We are also exploring additional educational opportunities that we can deploy into the marketplace to help patients understand more about their disease.
I think I'll answer the second one, Mark, which is around adjusting to the targeting. You know, targeting for us was heavily influenced by our DCC technology, right? Our DCC technology allowed us to apply very sophisticated analytics to help us understand the dynamics in the marketplace and who would be the most prone to prescribe Sunosi. We then took those analytics and aligned to our number of target lists. We are again focusing on the high potential prescribers, which, you know, is a culmination of many factors, but most prominently a very large patient pool, those who are very active and have high script volume, but also those who are active in WPAs. Those target lists, you know, we're actively approaching about 12,000 HCPs across all specialties.
One follow-up, Laurie. How can you comment further on how you are incorporating the DCC platform in the commercialization of Sunosi? Is this representative of how you will deploy the platform for AXS-05 and AXS-07?
It is. Remember, you know, our DCC platform is really a connected platform of technology-enabled tools and systems. What that means is that you have a fundamental base of tools that are available to the internal team who is analyzing data. We also have tools available to deploy to reps to make sure that their engagements with physicians are meaningful and highly effective. That is, you know, providing them data that they may not have had otherwise.
Thank you. Question about the SHARP study. What are the next steps if the SHARP study on cognition reports positive results? Related to that, how would having a label claim for cognitive improvement potentially impact prescribing of Sunosi?
Sure. We're really excited to unblind the study in the coming months to see what impact Sunosi could have on cognition. The study was initially launched by Jazz in response to feedback from physicians as well as patients. Overwhelmingly, patients do report cognitive dysfunction, which makes sense given that the patients do have fragmented sleep with excessive daytime sleepiness. If you look at the literature, it's been very inconsistent with regards to the impact of wake-promoting agents on cognition. Most of these agents have not shown any type of consistent effect. We are conducting a study. This is very much research. Now there is the potential for label enhancement should the SHARP study be positive.
That is something that we would absolutely seek to do to enhance the label. You know, first things first. Let's see what the data show.
Great. Historically, there was some DTC advertising, in particular on TV, and do we have plans to do DTC advertising?
Yeah. DTC TV advertising is not in consideration right now, but we are constantly exploring ways to effectively deploy media. By right now, I mean in the immediate near term. You know, as we continue to get our targeting approach correct, we will then switch gears and start thinking about how to continue to drive patients into the funnel.
Would you expect any changes to the sales force footprint for Axsome, assuming AXS-05 approval?
Yeah. No, not immediately. The two sales forces will stay completely separate and focused. I think especially if AXS-05 is approved, focusing a sales force at launch is very critical. Obviously, we cannot ignore the high overlap and potential for synergies. We will continuously evaluate that, and when the time is right, we will start you know, leveraging those call points across sales forces.
Great. Question from Joe Thome. How are you thinking about the ex-US opportunity for Sunosi, in particular, marketing the therapy in the region, yourself or partnering, et cetera?
Yeah, great question. Given that we have not closed the ex-US portion of the deal, once that happens, we will be prepared to, you know, to comment more on what our strategy is.
Great. We do have a few other questions pertaining to some of our other programs. We'll take the first one from Sarah at William Blair. Is there a focus on the use of reboxetine, so AXS-12 for OSA if there is such a high degree of comorbid depression?
We are developing AXS-12, which is reboxetine for the treatment of narcolepsy, specifically the treatment of the cataplexy symptoms of narcolepsy, as well as excessive daytime sleepiness. As a reminder, the results of our CONCERT trial did show a pretty profound and rapid effect on the reduction of cataplexy attacks. The study is ongoing and that is the focus of development of AXS-12.
Thank you, and now with respect to AXS-05, Joe from Cowen, if you are able to provide context for how long the labeling discussions may take, that would be helpful.
Great question. You know, we won't speculate as to how long this process will take, but as you can imagine, it is a top priority for the company, and our team is working expeditiously to bring this to a close as quickly as possible.
Great. Two final questions here before we round out the hour. For AXS-05, any color on timing for post-approval requirements, so post-marketing commitments and requirements? Apologies, that's from Charles Duncan from Cantor Fitzgerald.
I'm not sure that I fully understand the question in terms of the timing, but with regards to post-marketing requirements and commitments, the way that it works is those come with specific timelines from the FDA. They're agreed to, but then there's also a timeline that has to be met with regards to accomplishing those post-marketing requirements and commitments. You know, as I mentioned, in the prepared remarks, you know, we have started to honor some of those PMRs and PMCs already. I hope that gives you a sense of when the timing started or was required for some of those commitments and requirements.
Great. Last question, Jason Gerberry from Bank of America. For AXS-05, can you speak to whether the proposed product label is generally in line with the package insert that Axsome has sought to market?
At this time, we are in labeling discussions with the FDA, so we will refrain from commenting on anything that could influence those negotiations. I hope that you can appreciate that. In the meantime, what we can do is refer you to the recent publications of our efficacy trials, which have been published in high-profile peer-reviewed journals.
Great. That was the final question for the session.
Well, thank you all for joining us, today on the Sunosi webcast. I would like to especially thank our physician experts, Dr. Bogan, Krystal, and Faraone for their participation. As you can tell, we are excited by the prospects for Sunosi and its potential to deliver significant patient benefit and shareholder value. We're also very excited by the rest of our industry-leading late-stage CNS pipeline. We are looking forward to FDA action on our NDA for AXS-05 in major depressive disorder and to FDA interactions for our AXS-07 product candidate for migraine with the goal of a resubmission of that NDA. Our other product candidates are also progressing, including the ongoing clinical development of AXS-05 in Alzheimer's disease agitation, the phase III trial of AXS-12 in narcolepsy, and activities leading to a planned NDA filing for AXS-14 in fibromyalgia.
All in all, we have four pipeline candidates being developed in six indications which are either under FDA review or in late-stage development. We are committed to bringing these potentially life-changing medicines to people living with serious CNS conditions. We look forward to keeping you updated on our continued progress. Have a great day.
Thank you. That does conclude today's teleconference. We appreciate your participation. You may disconnect at this time.