Ovid Therapeutics Inc. (OVID) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the Angelman Syndrome and OV101 Seminar. [Operator Instructions] As a reminder, this call is being recorded. I will now turn the call over to your host with Dawn Schottlandt. You may begin.

Thank you, operator. Good afternoon, everyone, and thank you for joining today's OV101 seminar. Please note, we will have slides to accompany this call, which are also available through the webcast player on our website. We will also post the PDF of the webcast on our website following this conference call. As a reminder during today's call, we'll be making forward-looking statements. Various remarks that we make during this call about the company's future expectations, plans and prospects constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Forward-looking statements contained in this presentation may include, but are not limited to, statements about the progress, timing, scope, and the design of any future clinical trials for OV101, the progress, timing and reporting of clinical data of NEPTUNE or any future clinical trials for OV101, the progress, timing and results of any discussions with regulatory authorities regarding OV101, the potential clinical benefit of OV101, the future results of ongoing data analysis of NEPTUNE trial of OV101, the progress, timing and results of the clinical trials regarding the company's other product candidates; our progress timing and reporting of the ELARA open-label extension study and the company's future financial results and financing plans. Each of these forward-looking statements involve risks and uncertainties. These statements are based on the company's current expectations and projections made by management and are not guarantees of future performance. Therefore, actual results, outcomes, end results may differ materially from what is expressed or forecast in such forward-looking statements. Factors that may cause actual results to differ materially from these forward-looking statements include the fact that initial data from clinical trials may not be indicative and/or not guarantees of the final results of the clinical trials and are subject to the risk that 1 or more clinical outcomes may materially change as patient enrollment continues and more patient data becomes available. Additional risks that could cause actual results to differ materially from those in the forward-looking statements are discussed in the company's filings with the U.S. Securities and Exchange Commission, including the Risk Factors section contained therein. Such risks may be amplified by the COVID-19 pandemic and its potential to impact on Ovid's business and the global economy. Except as otherwise required under federal securities law, we do not have any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events, changes in assumptions or otherwise. I will now turn the call over to Jeremy Levin, Chairman and Chief Executive Officer of Ovid.

Thank you, Dawn. Good afternoon, everyone, and thank you for joining us. It's a pleasure to welcome you all to the seminar on OV101 for the treatment of Angelman syndrome. We're very excited to share this detailed overview ahead of what will be a transformative period for Ovid and more importantly, the Angelman community. With the outcome of our pivotal Phase III NEPTUNE study this quarter and its successful submission of a new drug application for approval of OV101, Ovid will have the opportunity to introduce the first ever therapy for this rare lifelong disorder, which was characterized more than 50 years ago. So let's get to it. Next slide, please. Joining me today on the call are several important guests. As you can see on this slide, we have some great presenters, including our 2 esteemed guests. Next slide, please. We hope to cover several important topics as outlined in this agenda. We will begin with Dr. Matthew During, who is the Chairman of our Scientific Advisory Board and a Founder of Ovid, as well as an accomplished and prolific entrepreneur and physician scientists. In addition to founding Ovid, Matt is a founder of Nightstar Therapeutics and Vector Neurosciences amongst other innovators. Matt has served as a Professor at Yale, Cornell and Ohio State University and is a visiting Professor of Translational Neuroscience at the University of Oxford. Following my remarks, Matt will describe the GABA receptor and its role in controlling central physiological processes of the brain, the most important one to us at this time, tonic inhibition. He will also describe OV101 and its role in restoring tonic inhibition to address the core cause of the pathology of Angelman. You'll then hear from Dr. Christopher Keary. Chris is the Behavioral Director of the Angelman Syndrome Behavioral Clinic at the Mass General Hospital for Children, the Staff Psychiatrist at the Lurie Center for Autism and the Assistant Program Director of the Multidisciplinary Clinic for Children, Adolescents and Adults with autism spectrum disorder at Mass General as well as the lead investigator for the NEPTUNE trial. Chris will walk us through the monumental challenges of caring for patients with this disorder throughout their lifetime and lend his perspective on what a first of kind therapy like OV101 might mean for patients and all those who care for them. Our next distinguished guest, Dr. Judith Jaeger, President and Principal Science of CognitionMetrics. Judy is an internationally recognized clinical neuropsychologist. She serves as the clinical Professor of Psychiatry and Behavioral Sciences, the Albert Einstein College of Medicine and an Honorary Professor at the Institute of Brain, Behavior and Mental Health at the University of Manchester. Judy will discuss the CGI score, its history and its meeting and how it fits into the pivotal NEPTUNE study. Following Judy's comments, Amit Rakhit, our President and Chief Medical Officer, will walk us through our clinical program and regulatory stages OV101 in Angelman and help orient you to our expectations for NEPTUNE. Lastly, Jason Tardio, Ovid's Chief Commercial Officer, will discuss the market opportunity for OV101 in this disorder. We'll conclude with a Q&A session. Next slide, please. Ovid has a broad pipeline, as you see in this slide, OV101 is our lead compound and the focus of today's discussion. As we announced this summer, Angelini Pharma is our exclusive development manufacturing and commercialization partner in the EU and certain other territories. As Ovid looks to commercialize OV101 in the United States with a successful outcome in the NEPTUNE study so to will Angelini within its territory, providing Ovid with access to over $200 million in milestone payments as the key outcomes are met plus royalties. We look forward to several milestones in the balance of our pipeline over the coming quarters, which will be a topic for future conversations. Next slide, please. With OV101, we have the opportunity to define the therapeutic landscape for Angelman syndrome, a rare disorder affecting some 500,000 individuals worldwide. There are no approved medicines for this disorder and until Ovid, no industry sponsored pivotal trials addressing it. As I noted, the Phase III NEPTUNE study is set to read out this quarter, with success, we'll move rapidly to get this medicine to patients. Our regulatory package, which Amit will discuss later, is expected to include an extensive safety and tolerability database in addition to efficacy results from the NEPTUNE, STARS and ELARA studies. OV101 enjoys patent exclusivity through 2035, and we see existing and potential partnerships as well as a potential pediatric rare disease voucher as multiple sources of future capital to support our global rollout of this product candidate. Now let's turn to how we got here. Next slide, please. Angelman syndrome was identified over 50 years ago, its genetic origins and physiologic manifestations are now well established. Historically, Angelman has been a difficult population to study and measure progressing. As normotypic scales and measures could not capture change in the multiple domains it effects. An important first step in the path towards therapeutic intervention was unraveling the role of tonic inhibition and establishing the tools to measure progress. From its early insights, next slide, please, Ovid was able to identify a key link between the pathophysiology of Angelman and the 101 mechanism of action. This is a pivotal moment in the journey towards delivering a new and potentially novel therapeutic. Next slide, please. But Angelman is a heterogeneous disorder, driven by a single mutation in multiple phenotypes, symptoms that baseline did not predict the area where a patient might see improvement. So a new global improvement measure was needed. Next slide, please. The STARS trial delivered that tool in 2018, and became the first ever successful study in this disorder. It established a proof-of-concept for OV101 in Angelman that could be confirmed in this pivotal study. Next slide, please, which brings us to today. With NEPTUNE on the verge of a clinical readout, a clinical and regulatory standard established and built around CGI-I for Angelman syndrome and the opportunity to deliver the first true treatment intervention in a patient population so deeply in need. Next slide, please. And all of this is happening this quarter. Now before I turn things over to Matt, I'll leave you with this quote which underscores the real challenge of Angelman syndrome, "I thought I'd have to teach my child about the world. It turns out, I have to teach the world about my child." We started from scratch with Angelman and we are very excited to be where we are today. And with that, I'll turn the call over to Dr. During. Matt?

Thank you, Jeremy. And thank you all in the audience who are listening to this and stakeholders, investors, and particularly, the families, the caregivers, the parents and individuals with Angelman. Without you, we wouldn't understand this syndrome, we wouldn't understand the brain as well we do, and I'm really excited to talk to you about some fundamental science that we believe shows the underlying pathophysiology of Angelman syndrome and how OV101 is a sort of unique special molecule that addresses that core underlying pathophysiology. I know a lot of you in the audience aren't scientists and relatively laypeople. And so for those of you who do have a more comprehensive understanding, I apologize if this is very high level and basic, but I think the goal here is to get a full understanding from everyone who's listening today. So you can understand our excitement about this and sort of understand what we think is the core mechanism underlying Angelman syndrome and why we believe so strong in OV101. So the next slide, please. It's really the life of the scientists that you get to make basic discoveries in the lab that move towards the clinic, and this is one example where this happens. And of course, it's very fulfilling to us to be able to develop this molecule and take basic fundamental insights from the lab to the clinic. Next slide, please. So first of, I'd like to talk about GABA, and I'm sure most of you've heard about GABA. Brain, as you know, signals in 2 nodes, both electrically and chemically, 1 brain field talks to the next by releasing a chemical messenger. We call that a neurotransmitter. And within the brain, the most important in the core inhibitory neurotransmitter is a molecule, GABA. And when it gets released, it can activate on 2 types of receptors, what we call synaptic receptors and extrasynaptic receptors. And this overall signaling regulates excitation and inhibition. It's balance between excitement like fire in the brain and water on the brain that needs to be tightly regulated to have information processing within the brain. And so the brain operates in a way where we're engaged with environment in a way that enable us to grow, to build up and function on every domain that we understand that the brain carries out. So typically, differentiating between synaptic, which really mediates what we call phasic inhibition is very fast, is point-to-point, how it typically, for many, many years, that was felt to be the only way the brain operator that we've talked -- 1 cell talk to another that synapses occurs within a millisecond time frame and the short burst and regulates communication like that. More recently, over the last decade or so, we've understood more and more about the so-called extrasynaptic receptors. These lie outside the synapse, and they have a different function. They're sitting the global tone, that's why we call it tonic inhibition. They provide long lasting inhibition, and this really stands to maintain the optimal signal-to-noise that we get system fidelity. In the next slide, we'll sort of talk about this a little bit more and the role of Angelman syndrome. So next slide, please. So basically, in Angelman syndrome, we all know that Angelman syndrome is a genetic disease -- genetic disorder, which is caused by either deletions, mutations or variations of UBE3A gene and the deficiency of UBE3A is really what all individuals with Angelman syndrome share. But that's just a gene, how does that translates in ultra brain and ultra development and ultra function? Well we now understand that one of the key targets for UBE3A is the so-called GABA transporter. And when you have deficient UBE3A, you increase this transporter. That transporter mediates GABA uptake, so this increase GABA reuptake. That means, as you can imagine, decreased extrasynaptic GABA particularly. So even though you have the uptakes mediating effect on post synaptic and extrasynaptic and the synaps, there's minimal level of concentrations of GABA. So even if there's slight variations in the transborder, that doesn't really impact on the synaptic signaling, but it has remarkable dramatic effects on the extrasynaptic signaling. When you lose that extrasynaptic, when GABA has no longer be an extrasynaptic space, it can't activate those extrasynaptic receptors who then have decreased tonic inhibition. And this means that brain gets extremely noisy, it becomes inundated undated with all sorts of excitatory signals and resulting in a wide range of symptoms. Next slide, please. So one way I'd like to view this and sort of make it simple. And so I can understand and I hope that this makes sense to you as well. Let's look at an analogy here, and we've got a radio. And so you can imagine when this insufficient tonic inhibition as there is an Angelman syndrome, it's like having a radio, you've got a lot of noise and sort of you've got this chatter going on. You can't hear any -- you can't hear the channel, you can't hear the signal. If you tune out that noise and you quiet all that chatter that's going on, all of a sudden, you get a clear radio signal, you've got this optimal signal to noise. If you actually filter it down even more and you turn the brain to a point where you basically going to the noise, you lose the signal as well and that you get radio signs, you can't hear it. And this is how the brain operates. We know this even. Very elegant experience carried out at an experimental animals but this is what's going on. And we also understand that this is the fundamental deficit, when you look at the Angelman brain and you look at the animals that model Angelman syndrome that have a knock out of the same gene. So when we look at those animals, just as we look at humans with Angelman, we don't see anything grossly long. When you look at the brain, morphologically, everything looks okay in the brain. And as you put an electrode in and you look at how the cells are joined together, they look -- that looks okay as well. But what really stands out is this loss of tonic inhibition. And that's why we believe this is the fundamental underlying mechanism. Next slide, please. So with tonic inhibition, tonic inhibition occurs throughout the brain. As Jeremy mentioned, every cell, every neuron in the brain has affected this disease. And where that loss of tonic inhibition impact is really what results and what symptoms we see and what disorder occurs. This often occurs within the hippocampus, amygdal and limbic brain that regulates memory and anxiety. If it occurs in the cortex, cognitive behavior, communication, language as that's impacted in the cerebellum that's controlling motor coordination and finally the thalamus, regulating sleep and wakefulness and circadian rhythms. So this occurs in every individual. That's why we call this disease very [indiscernible] in any given individual, one or more of these complexes and symptom demands will change. Next slide, please. So OV101 is a very unique, a very special molecule. It's similar in structure to the GABA molecule itself, but it's confirmational very rigid. Next slide gives us its unique specificity and its specificity is just to the extrasynaptic receptors that binds -- where GABA bind and so competes with GABA and that provides it a very, very important property that we'll discuss a little bit more. And particularly, that is that unlike every other GABAergic drug that's currently in the clinic or in development, it's the only drug that acts in this way and it actually activities [indiscernible] in those types of brains where there is lowest amygdala. Where the GABA levels are low, this drug has greatest effects. Where GABA levels are high or normal, the drugs effects attenuated, weakened. So although no drug that gets in brain, you can say it's a smart drug, OV101 is unique in that it actually works greatest and [indiscernible] brain it's a most fundamental problem. So where there's lowest amygdala that will restore GABA signaling in those. There's normal GABA and will have minimal effect, and that's one of the reasons we believe drug is so well tolerated. So next slide, please. So this is supporting what we've described with the previous slide, we gave the picture of a radio. Here, we're actually having data that drives straight from peer reviewed publications, which sort of gets strong preclinical support. So that level of the need to have optimal tonic inhibition. So on the left-hand side, this is looking at system's ability, looking at actually how the brain operates with changes in environment with an experimental animal and showing that the brain is responding appropriately to those external stimuli. And here you can see on the left, you've got insufficient tonic edition just as you do have an Angelman syndrome. And you can see that there's just reduced signal to noise. You actually got a noisy system there. When you increase tonic inhibition at the peak there, then you've got the excessive noise. If you go too much tonic inhibition, then you lose that optimal signal to noise. On the right-hand side, we're now seeing data from an Angelman syndrome mouse that models very tightly in clinical condition, and you can say we see the phenomenon that if we actually give a low dose, relatively low dose as we're sort of modeling with the QD dose in that clinical trial that you're there about. At that level, you're seeing optimal tonic inhibition, and you're seeing improvements in behavior as shown by a motor function. And if you go beyond that, you actually start to lose the benefit. So this so-called inverted U phenomenon is not uncommon in the context of when you're dealing with a physiological process like tonic inhibition. Next slide, please. So further proof concerning -- further data to support why we felt so confident going to the clinic that we're likely to see a signal was actually work on the Angelman mouse, which has a very distinct motor phenotype and motor behavior or motor function that parallels what we see in Angelman syndrome itself that impairment in posterior, movement in gait. And this model is very well characterized. And then we can look at the animal, we can give it OV101 or we can give it a controlled drug over a vehicle. And you can see in this particular slide, you can see in the middle where the UBE3A deficiency and this Angelman, you can see the sort of posture where it's sort of flexed up and that's a very abnormal. A normal healthy control of what we call a wild-type mouse just hangs there straight down and that's normal. When you give OV101, you can see that posture being corrected. So we saw this effect and see effects on data. We don't have time today to go into greater detail, but also effects on gait as well and movement. And so with this well-characterized model, we're seeing restoration of function, what we call finished of the correction. And so that gives us much -- some sort of faith that when likely if the model is what we call predictive validity, we believe this is likely to show similar benefit in the clinic. So next slide, please. So in summary, what I've tried to work through is that extrasynaptic receptors, and these are ones that contain a delta subunit are responsible for tonic inhibition in the brain. They set the overall tone or sensitivity of the system to ensure optimal signal to noise. And that signal to noise ratio at the time is what really controls what we call system fidelity enables an individual to interact smoothly with the environment, to grow, to develop, to reach milestones. So this is a fundamental, underlying, physiological process that enables an individual to grow and develop normally. OV101 is highly selective agonist of those delta subunit GABAA receptor agonist. It has a unique mechanism with greatest activity with low ambient GABA. So lower the GABA, greater need, the more the drug works. Normal areas, brain gets weaken, has minimal activity. So you take this drug, you don't immediately fall into sleep or go into coma as you'd have with a drug that actually acts with GABA levels are higher. Preclinical work emphasizes what we call the Goldilocks phenomenon in other words, too little is not good, too much is good, you want just the right dose and avoids excessive tonic inhibition and desensitization when you've repeated the administration of this drug. It's exactly what we saw in the clinical trial when we moved from QD to the BID dose, the effects have weaken as you have extrasynaptic tonic inhibition and as the systems defense value. Next, we see restore tonic inhibition and correct motor function in the Angelman syndrome mouse models, and we feel this data gives us compelling reason to be accordance to the clinic and a strong scientific rationale for clinical translation. Thank you. And with that, I'd like to move forward and pass the call over to Dr. Chris Keary.

Okay. Thank you, Dr. During. So my name is Chris Keary. I'm a Child, Adolescent and Adult Psychiatrist and the Behavioral Director at the Angelman Syndrome Clinic at Massachusetts General Hospital. I see kids, teens and adults with Angelman syndrome there for the development of treatment plans for behavioral concerns in Angelman syndrome and see many of those individuals for ongoing care are probably seen over 100 patients with Angelman syndrome. And it's my pleasure today to be talking with you a little bit about Angelman syndrome and the manifestations of the syndrome, how it can present, how it affects the lives of people with Angelman syndrome and their families. And what are the needs, I would say, in terms of treatments as some of the cares for patients with Angelman syndrome. So I'm pleased to be able to talk to you about that today. Next slide. Okay. So Angelman syndrome is a genetic disorder that has, as its consequence in neurodevelopmental syndrome. And there are no current approved therapies for the core pathophysiology of Angelman syndrome. It is a disease that a fair amount of the genetics behind it. It results from a loss of function of UBE3A protein, and that's due to a loss of function in some way of the UBE3A gene on the maternal chromosome 15 and one of the downstream effects of the loss of function of this protein is decreased extrasynaptic GABA levels that lead to decreased tonic inhibition. And that's thought to be 1 of the factors in the resulting downstream clinical phenotype of Angelman syndrome. And as a neurodevelopmental disorder, symptoms of Angelman syndrome are present within the first couple of months of life. And are expected to continue with patients throughout their whole life into adulthood. Despite the diagnosis really being understood in the mid 1960s by Harry Angelman, there have not been any approved therapies for the core of what the syndrome is itself specifically for Angelman syndrome. It affects about 1 in 15,000 people. And it's syndrome where oftentimes many different specialists need to be involved in the care for that individual. Neurologists, psychologists, speech therapists, occupational therapists, physical therapist nutritionist, individuals and Angelman syndrome acquire multidisciplinary team of multiple different clinicians caring for them. Moving on here to the next slide. I want to talk with you now a little bit about the core features of Angelman syndrome and how this neurodevelopmental disorder can present, a little bit about what these individuals and their families struggle with. I'm going to start with your just drawing your attention on this slide to the top right, the learning box. I'd like to start with this one to really drive home for you all that individuals with Angelman syndrome or patients with Angelman syndrome have impaired cognitive function as a result of the diagnosis. And another term for that is intellectual disability and the old term for that mental retardation. And that results in impairment in a lot of different cognitive domains, particularly learning. Individuals with Angelman syndrome struggle with learning new skills and activities. And for people with Angelman syndrome, they require help their whole life with basic activities of daily living that might include dressing themselves, feeding themselves, toileting, showering, they're expected to need help in those areas into adulthood for many patients. And so they really are going to require lifelong care and support because of this intellectual impairment, which is characteristic for every person that has Angelman syndrome. A component of that is impaired communication. The next section, I'll tell you about here. The vast majority of patients with Angelman syndrome have major challenges with communication, with the majority of patients with Angelman syndrome being either a completely non verbal or having a very small number of words that they may use somewhere between 1 to 5 words, so mama or ball or pool or parts of words that they use consistently. And so for the majority of patients with Angelman syndrome, there's very little in the way of verbal expressed communication. And one of the things that's particularly hard about this syndrome is that patients with Angelman syndrome frequently have better understanding of language than they may have in terms of normal expression. And that is we think really frustrated for a lot of kids, teens and adults with Angelman syndrome who may want to be able to convey their wants and needs and don't have really good strategies or ways to be able to do this. And that can contribute to a lot of the challenges that many patients with Angelman syndrome have with behavior. The next section here. It's not unusual for aggressive behaviors to be seen in kids, teens and adults with Angelman syndrome. Partially potentially driven by frustration around not being able to convey themselves. Hyperactivity is extremely common in this syndrome, challenges of hyperactivity, easy distractibility. And for many people with Angelman syndrome, this will persist into adulthood problems with extreme impulsivity and hyperactivity. That make an individual Angelman syndrome at risk if they're not really very closely supervised throughout the day by staff or their family. Another really consistent factor for the majority of patients with Angelman syndrome are problems with sleep. The problems with sleep and Angelman syndrome are extraordinarily severe, even among other people with developmental disabilities, like autism or Down syndrome or Fragile X syndrome, which you may have heard of. The challenges are falling asleep, staying asleep through the night and the total amount of hours in individual with Angelman syndrome get, which can be extraordinarily low. In some individuals, 4 hours of sleep and night. You can imagine what it would be like to be a caregiver or a loved one or a parent for an individual with Angelman syndrome if they're getting so little sleep at night. It is even among other developmental disorders, extraordinarily profound challenge. Seizures are very common in Angelman syndrome with up to 85% in many studies of patients with Angelman syndrome having seizures at some point in their lives. The seizures can be, for some patients with Angelman syndrome, harder to treat, more refractory to usual treatments and require being on multiple different antiepileptic medications. Motor function, the last section I'll tell you about here is also a common feature in Angelman syndrome. There's more variation here, patient to patient. There are many patients with Angelman syndrome who can't even pull themselves up to standing and put weight consistently on their legs to be able to walk. And then there are some patients with Angelman syndrome who can walk, but going upstairs is a challenge. And then some patients that can go upstairs and walk and even run or with little in the way of support. However, even in patients whose motor functions may be better, there are a lot of challenges with tremors. And what are called -- what's called myoclonus, which are these whole body sudden jerks that can happen and are more common in Angelman syndrome. So that may make a person with Angelman syndrome whose motor function is pretty good, make it much harder for them to do basic things like hold a cup and drink out of it or to be able to let's say, use a fork and a knife, for instance, if they're trying to feed themselves. And so these challenges around tremors or myoclonus can make individuals of Angelman syndrome require a lot of additional support around basic health care skills. So that means that all of these different categories, all these different core symptoms all getting different separate treatments to try and address them. And we're hoping that the direction forward for the treatment of Angelman syndrome will be treatment that address the core features of the diagnosis and that have downstream effects on all of these different categories that further we hope for the future. Next slide. Here in the section of the slide is all the different things that I've just talked about in terms of the different areas of impairment. And if you put this all together, the result is that individual of Angelman syndrome required constant supervision and a lifelong care. And are anticipated to require really as much close supervision and support in their adult years as they oftentimes need in their childhood years. And that supervision really may need to be for the majority of individuals, 24/7. There's a lot of medical need in terms of care that they require, but there's a lot of effects on their lives due to this morbidity. I'm just going to mention a couple of the different effects on their lives that I want to share with from my own practice and care. So individuals require oftentimes 24-hour care for life. There are a large number of medical appointments that are required. If you think about all the different specialists and all different therapies, people with Angelman syndrome are receiving, that is a full-time job for a parent or a caregiver to just get an individual with Angelman syndrome to all their appointments, supervise them. And it's an extraordinary burden for caregivers, oftentimes impacting a caregiver, a parent's ability to work themselves because it's -- coordinating this care is its own full time job. And the caregivers themselves oftentimes need support, siblings need supported. I think if a family member were here right now to talk to you about their experience, they would say there are a lot of joys and care for a person with Angelman syndrome. They tend to be individuals of Angelman syndrome very affectionate and socially driven people. However, there are a lot of challenges, too. And it is a large amount of stress for caregivers. One of the other effects that there can be for individuals of Angelman syndrome is because they need to focus so much on these different therapies, they get less time to kind of be a kid, less time to kind of be an adolescents, less time to be in the general educational environment with their peers when they're at school, for instance, they just have more fun social time because they've got to be focusing on physical therapy, speech therapy, occupational therapy. There's more challenges around, I mentioned the effects of stress and maybe even anxiety and depression on caregivers. But we're increasingly learning the ways in which anxiety is a challenge for patients with Angelman syndrome too. They get very upset and distressed with separation from a caregiver, and that may be something that drives aggression and/or crying episode, so things like that. And then, of course, the financial strain on families, the reduced ability for family members to work because they're providing care for patients with Angelman syndrome. All the different therapies, we're going to talk a little bit more about, but I want to also impress upon you that these therapies are always covered by insurance, especially for adults. And many families are having to pay out-of-pocket for the therapies that they know -- that like things like physical therapy that may be harder to gas more adults. So there can be real financial impact. These supports aren't always covered by insurance. okay, I'm going to move on to the next slide here. Let me share a couple of quotes for you from families that I've worked with over the years. The first quote here, "It's a full-time job for his family and teachers. He can never be out of our sight even for an instant. It's too dangerous for him." This highlights a 14-year-old I work with who had such a risk with falls and has so much impulsive running that, that individual would do, but they were at constant fall risk, requiring that a teacher really be on them constantly throughout the day. The next quote here, "I'm so tired of having to educate my daughter's doctors and teachers about Angelman syndrome. I wish more was known about how to help these kids." I think there's an additional challenge, if your loved one has a more rare genetic syndrome, because you're having to educate doctors oftentimes, particularly when there's so few available treatments that doctors are even aware of. And then this last quote, "Thank you for working with our Angels. It means a lot to know that people are working to try and learn more about Angelman syndrome and help." This is a father who's moved to tears about the fact that people were -- researchers and therapeutic teams are finally showing more interest in developing therapeutics for people with Angelman syndrome. And then move on to the next slide here. And talk to you a little bit about treatment, talking first about medications. So there are no current approved therapies for the core -- the pathophysiology of the core symptoms of Angelman syndrome. It is still treatment that's oriented around trying to get at addressing some symptoms that are part of Angelman syndrome, but nothing that's really thought to address the core pathophysiology of the diagnosis. And there are efforts towards prescribing medications to help with some of these features here, but there are real challenges with them as well that I want to tell you about. Those challenges are that medications that can be helpful for other patients with other neurodevelopmental disorders can be harder to use in Angelman syndrome. Those treatments can be less effective and can be more prone for side effects. Because of how sensitive this population can be to adverse reactions to medications. I want to first talk to you about behavior because this is a lot of what I do as a prescribing clinician for patients with Angelman syndrome. Hyperactivity, aggression, anxiety, these are major challenges for many patients with Angelman syndrome, and we know that from large epidemiologic studies looking at, okay, what are the problems for this group of 100 adults with Angelman syndrome, excuse me, for instance. And what I can tell you is that it is extremely hard to prescribe some of these medications that are helpful for other neurodevelopmental disorders. For instance, psychostimulants, methylphenidate, mixed amphetamine salts, Ritalin and Focalin, you may have part of those medicines. So those medications are extremely hard to use in my clinical experience. And then many other clinicians who care for patients with Angelman syndrome. It's rare to find a person with Angelman syndrome who could tolerate a standard of care treatment for hyperactivity. Same thing with antipsychotics, which are very helpful for aggression in autism, medicines like risperidone, aripiprazole, quetiapine which, in my experience, are more likely to cause motor side effects in Angelman syndrome, worse motor function, worse gross motor abilities that makes those medicines almost completely off the table for many patients with Angelman syndrome. Or you may end up needing to give dosages that are so low that it's not really effective. When it comes to sleep, there was a trial that showed improvement with melatonin. However, that's not been the case for many patients with Angelman syndrome. I have a lot of experiences of when I hear sleep is a problem asking families, have they tried melatonin and getting watched out by the parent because we tried that a long time ago, it stopped working a long time ago or it never worked for our son with Angelman syndrome. So a lot of other medications are tried, alpha-agonist, benzodiazepines, the serotonergic-acting medication trazodone. However, these medications, I have many patients who have just completely not responded to those medications, while they would respond to the same dosage if they didn't have Angelman syndrome and had another neurodevelopmental disorder. So I struggle a lot with helping families with sleep with current medications. And there are challenges with seizure medications as well. For instance, valproic acid, which is Depakote, can significantly worsen motor function, and that's a really standard of care treatment seizure disorders. It's more often as many patients with Angelman syndrome need to end up on multiple seizure medications. That's not uncommon at all. So there are real challenges with what we might think of as symptomatic treatment for Angelman syndrome. Moreover, I really want to impress upon you that because this is a non verbal or minimally verbal population, families are worried about starting medications for their loved one with Angelman syndrome because they worry that they won't be able to tell that if they're having a side effect. So I get asked all the time by families, look, as this medicine has been studied in Angelman syndrome. The answer is usually no. So to have a potential treatment that's been studied and done to have a favorable safety profile in Angelman syndrome. That's an extraordinarily reassuring thing for me as a clinician and for the families that I work with. I'm going to move on to the next slide and tell you about non medication, sort of symptomatic supportive care. These are some therapies that get offered to patients with Angelman syndrome physical therapy, speech therapy, occupational therapy, behavioral therapy. They may be delivered if it's at a school, at a special need school or it may be -- these may be delivered as well at in a separate classroom in the public school system. The challenge with these therapies is that there are a lot of other aspects to Angelman syndrome that limit some of the efficacy of some of these therapies. For instance, I told you about challenges in hyperactivity or aggression, that can really slow the progress that a child makes in physical therapy or speech therapy. If you think about it, like I have some kids at work with Angelman syndrome, who can only participate in the therapy for 3 minutes at a time. And that's -- that really slows the progress that you make in those. And families are used to if they see progress of these therapies, having it be something that takes place over years, a really slow process. And then move on to the next slide here and talk to you a little bit about adults. Over on the left side of the slide here, you can see a graph where in the x-axis is age and the y-axis is a percentage of individuals with Angelman syndrome. And if you look at here, you see, as the individual of Angelman syndrome grows, they are more and more likely to have to be in a residential facility. A lot of family members or parents of children with Angelman syndrome if they become adults, don't want them to necessarily go into a residential program. They'd like to care for them at home. They may feel like that's not in their values to choose a residential program, but they're forced to choose it because the care needs for an adult are just too much for the parents to be able to bear. So there is a real need for effective treatments for the core symptoms of Angelman syndrome as much in adults as there are in kid. And moreover, the more challenges there may be, particularly in behaviors in individuals of Angelman syndrome, the more likely you can see things like significant anxiety or clinically significant depression. And this was one study that saw higher levels in mothers than these are certainly higher numbers that you'd see in the general population in terms of anxiety and depression. So there's a real effect of caregiver stress. I'm going to move on to the next slide here and just talk to you a little bit about things specific to the adult years for patients with Angelman syndrome. For many with Angelman syndrome, there's a loss of even the symptomatic treatment I was telling you about physical therapy, occupational therapy. Those are a lot harder to get covered by insurance for adults with Angelman syndrome as compared to kids. So there's oftentimes a removal of the therapies that we know can provide some improvement in some of the symptoms. And so that can cause things like regression. So there's really the need in adults in some ways, it's perhaps even more than it is in kid in terms of some things that are -- address a core symptom. A lot of parts of the country don't even have residential programs to be able to support families and to give them the kind of support they need to do adult bit or residential programs may never -- may not know anything about Angelman syndrome, they might know a lot about autism than Angelman syndrome and may need a lot of education from parents and caregivers. I would say, if anything, medications are used to try and address these kind of symptoms of Angelman syndrome more often than adult with more likely to end up on polypharmacy or medicines that help a little bit, but not a whole lot. And the behavioral consequences of the disease, things like aggression, hyperactivity or anxiety are more impactful if they're done by an adult compared to like a 7-year old kid where aggression may be easy to redirect, but a lot bigger a concern in a 27-year old. So I'll move on to the next slide here. OV101 is a highly selective oral extrasynaptic GABAA receptor agonist, which works to improve signaling regulation through the brain. It is proposed to be a treatment that addresses the core features of Angelman syndrome by addressing the specific pathophysiology of the disease. I want to really impress upon you all today that small changes can have an extraordinary effect in terms of clinical benefit for families -- for individuals with Angelman syndrome and their families. I think there's a lot of concern on the part of clinicians like myself, work with people with Angelman syndrome and families themselves, that the outside world look at -- may look at small -- what they perceive as small changes and miss how extraordinarily impactful they are for those families. I'll give you an example, if an individual Angelman syndrome can only focus for 3 minutes due to hyperactivity in physical therapy, think about the kind of progress they could make if they could focus for 10 minutes. So the outside world, they might say, well, is that a big difference, 3 minutes to 10 minutes, it's an extraordinary difference for these families, for these individuals and their families. In terms of what it might open up for them. If you improve motor function a little bit and you reduce the frequency of falls, that's also an extraordinarily important thing for families and reduces a lot of risk for that individual. So small changes can have an order of magnitude effect on families. One of the challenges with studying Angelman syndrome is that it can, you see different severity like, for instance, in motor function from one individual in Angelman syndrome to another. And we're hoping that treatments that are helpful for the core features of Angelman syndrome will affect multiple different core symptoms of Angelman syndrome. So you need a good standardized way to measure that improvement when it's so heterogeneous. And also to capture, if a small change from all the others is really meaningful to that family. And that's where I think the local global impression improvement, the CGI-I scale is, I think, a very important tool to look for improvement in this population. Because you can capture a change and assess how significant it is for the family and to the evaluator. And also, there's a lot that's been done to use objective clinical criteria and a lot of rigorous training for the evaluators to ensure consistency in one evaluator to another that allows you to really get a sense of the impact of treatment. And that's what's most important. We want treatments to be impactful, not just whether they changed some rating score by a point or 2, whether they've made a change in their lives, and that's what the CGI-I can address. I'm aware of my time here, and I want to make sure I pass it over to Dr. Jaeger to talk a little bit more about the CGI. I really appreciate your attention today. And your interest in this patient population, I can let you know that families are very excited to have us thinking about treatments. Thanks so much today.

Thank you, Chris. So I'm here to talk about the CGI, or the clinical global impression scale. There are 2 versions of the scale, the severity scale and the improvement scale, they're used in tandem together. The CGI is an instrument that has been around a long time. It was developed initially in the '70s. It's a valid and reliable measure. It's used -- has been used for the measurement of effects of medicines on a range of clinical disorders, including bipolar disorder, schizophrenia, autism and many others. It is accepted by regulators. And indeed, its development was somewhat initiated by regulators and researchers who were concerned about disease-specific rating scales. So it is well-respected as an endpoint. So to go to the next slide. In history, I always find history as useful for understanding where we stand with instrument development in neurobehavioral disorders. Typically, when we started in the field of clinical cyclo-pharmacology trying to measure the effects of treatment, we developed disease-specific rating scales. These are instruments that are validated and reliable. That are used to measure the severity of symptoms or a constellation of symptoms of a particular disease. So these are disease-specific instruments. One of the problems with disease-specific instruments is that they're basically a collection of items. So for example, in a depression rating scale, there will be a depression item, there will be an anxiety item. There will be items around sleep and other somatic signs. And what we do is we rate each item, we add them up, and we have a total score. The problem is we don't really know about whether the weighting of these scores is appropriate. So if the depression item improves enormously and the sleep item doesn't improve at all, does that mean our drug didn't work? So because we're concerned about weighing things appropriately, there was an effort -- a call really for a global scale. So CGI was really developed as a solution to the problem of item weighting in disease-specific scale. The idea was, could we have a highly reliable and valid tool that captures the gestalt, the whole overall clinical impression of disease severity and change over time, that wouldn't rely on the concerns about item weighting in a disease-specific rating scale. So that was done. And as I pointed out earlier, adopted and very widely used well over 50 years in regulatory trials for a range of disorders. In fact, it gains such respect in a way that its application to specific diseases then evolved. People started to say, well, this scale is so effective at capturing the global, why don't we go in and create disease-specific criteria for the various anchors. And even disease-specific semi structured interviews to make sure that we capture the same thing in every patient, again, to improve the reliability and validity and initially in affective disorder, schizophrenia and Alzheimer's disease, where the scale has been used in the broader sense at the outset. This process paved the way for where we are now. So now for the first time in history, we're contemplating treatment for neurodevelopmental disorders, a really new world. And with Angelman being one of the important ones of these. And we're faced with the same measurement problem that psychiatry had all these years ago. But now we benefit from the fact that psychiatry has been using this approach to measurement of -- to reliable measurement of clinical benefits now for many years. So we can go to the next slide and talk about the CGI and why it's optimal really as an endpoint for Angelman syndrome, obviously adapted for Angelman syndrome. It's primary -- it's -- sorry, it's optimal as a primary endpoint, in particular, under certain conditions. One is in disorders that are rare. And why is that? Because developing disease-specific rating scales will take very long, complex process, and it requires many, many subjects. You need hundreds or thousands of subjects to develop and validate a new disease-specific scale. And the emergence of effective treatments is happening at such a pace that we would flow treatments down if we even attempted such a thing. But more importantly, Angelman is one of the neurodevelopmental conditions with unusually large phenotypic heterogeneity. So what would be the universe of items that would constitute a disease-specific rating scale. There would be so many items, and we would have no way of knowing how to weight them. And so for this purpose, approaching the CGI as the framework for a primary endpoint is certainly optimal and was seen so also by regulators. So with that decision made, the development of a disease-specific anchored CGI for Angelman syndrome was undertaken, and it has now been specifically standardized and adapted to study Angelman syndrome. And that work was done in consultation with clinical experts in Angelman syndrome as well as caregivers and thereby incorporating their observations into the scale itself, the interview methodology and the criteria for assigning a particular rating. And I'll show examples of that later. Integrator reliability has been established and sensitivity to treatment effect, which is the most important form of validation of the scale have all been established. The other advantage of using a CGI as opposed to a disease-specific rating scale, even if one has one, is that by definition, the clinical criteria in -- to demonstrate a change or an improvement in CGI or by definition, clinically meaningful. Because the observer can clearly see it. That's what the improvement score means. And so now again, you have a scale where we know what the change means. It means it may not tell us specifically where the change was for a particular patient. But it tells us that they could stop the overall picture has improved to a degree that's significant enough that it can be detected reliably by a trained and -- by a trained clinician. So the next scale shows us how it works. So the therapeutic effect of a drug is measured by the change from a baseline position. So the first step is the CGIS or severity. And we estimate the CGI-S score based on an exhaustive, semi-structured interview of a set of domains that were identified by disease area experts and families and caregivers as the most important, the most clinically meaningful domains. Each domain is then investigated through interview and observation in an exhaustive way. And I will show you an example, anchors are then provided that help us position the patient along this continuum of 1 to 7. 7 is a severe case, and 1 is a clinically healthy individual. And so obviously, by definition, if you have Angelman syndrome, you're not going to have a 1 on the CGI-S. In fact, you'll rarely have a 2 on the CGI-S. But in any case, the process involves writing exhaustive notes in this structured form, reviewing each of the major domains, which then justify the CGIS rating but also form the basis for the CGI-I rating in the subsequent visits. So the CGI-I is administered with the baseline CGI-S note present and available to the clinical rater. So CGI-S is the starting point. And then the CGI-I is in reference to that starting point. So let's look at the figure below. You will see a 4 as baseline. What that means is that there has been no change. So I have now conducted the CGI-I interview, having reread all of the notes from the baseline CGI-S interview that was done prior to dosing. And I'm making a determination as to whether I see a change overall after systematically reviewing the 4 domains. And if I rate a 4, it means I'm seeing essentially the same thing I saw at baseline. If I rate a 3, I'm seeing some improvement from baseline. If I rate a 5, it's somewhat worse from baseline, and there are anchors for these change points. And so forth, a 6 is quite a bit worse and a 7 is very much worse. And on the other hand, a 2 is very much better. And a 1 is something we're not going to see in a clinical trial in most instances because it's essentially a return to normal. So the change score becomes one of no change, worsening or improvement. And it's that change score that gives us an indication as to the effect of the drug when we compare those on active versus on placebo. So we can go to the next slide. So the CGI-I is now being rated in 4 domains. We're rating behavior; motor functions, both gross and fine motor; communication; and sleep. And for each of these domains, experts and informants has given us prompt that will bring out to the clinician who's performing the rating those symptoms and signs that are the most troubling to them and the most clinically meaningful. So the CGI-S has been done at this point, and each of these domains has been rated. And now the CGI-I goes through each of those domains and provide a judgment as to whether improvement or worsening has occurred since the last visit or since the baseline visit. The next slide gives you an example of how this works. So under fine motor, you'll notice that there are very specific anchors. So a severity level of 4, this is now the S, right, this is the baseline, is a moderately impaired person with Angelman syndrome. And this is what it looks like in Angelman syndrome. This is what's important here. This is an Angelman syndrome specific set of anchor developed by experts in the field to understand how this disorder presents. And we have specific anchors for fine motor and for gross motor. If we go to the 4, the moderately, so for fine motor requires hand over hand assistance to use utensils to eat. Okay. So what would be an improvement over that? Not requiring hand over hand assistance, being able to use utensils independently or using less hand over hand assistance and so forth. It's really quite objective. You see it's not purely -- I mean, it's, of course, a clinical judgment, but no less a clinical judgment than listening to the pulse in a sphygmomanometer to determine your cutoff values for measuring blood pressure. It's an expert judgment, but very rigorous anchors are provided. And the same can be seen with the anchors for gross motor. And what those rigorous anchors do is it allows the clinician -- well, it facilitates into rate of reliability. So we're going to have high levels. You're not going to have major disagreements between raters when you have anchors that are this precise. And we don't see that. We get high into rate of reliability, which assures us of the validity, validity is limited by reliability, assures us of the validity of the instrument as a measure of treatment effect. So we can go to the next slide and just demonstrate how the CGI-I then follows that CGI-S rating. You go through the same set of domains. And in this case, this isn't really effect similarly of the form, but you can see what happens. This is a large form, and there's lots of space, and we want lots of narrative. So for each domain, for the CGI-I, I'll give you an example from motor, the clinician is asked to list clinical symptoms that have improved or worsened since baseline, and they need to record all the sources, who said it, was it the teacher? Was it the occupational therapist? Was it the parent? Is the clinician observing it? And details around the frequency, the duration or intensity of any change, of any difference since the last visit. Again, remember, always referring to the narrative from the CGI-S for the motor domain, so that the reference is there. You're not relying on your memory of what they looked like the last time. You're comparing the current description to the observations, and you're recording those observations, which also offers an outstanding quality control opportunity for a clinical trial. We can check these to see that the rating is comport with the observation. Okay. So this form is completed by each clinician in performing the CGI-I. And the next slide then shows you how the CGI-I overall global rating is made. And once again, the clinical criteria are very clearly outlined. And in this case, the global score requires that the clinical rater bring to bear all of the domains. So considering everything together, behavior, motor, all of the domains. Is this person different? Was there no change from the baseline? Once again, referring to the CGI-S or was there an improvement or a worsening and to what degree? And that degree tells us the change over time that we're going to see in the trial. So the CGI-I, as illustrated here, in summary, is a reflection of the change from the CGI-S at baseline. And as you'll notice, a rating of 4 would indicate that, upon my subsequent examination, I see no change from where this patient was in the aggregate as a gestalt on the 4 domains. I see no change overall. Anything to the left of the 4 means I see an improvement, and anything to the right of the 4 suggests a worsening since the baseline assessment. At the level of the individual, an improvement would be a 3, a movement from a 4 to a 3. At the level of the group, we would be looking at a value anything less than 4, right? That would be the average. We can examine -- the statisticians will have opinions about different ways of examining and analyzing these data. In terms of effect size, any value less than 4 suggests overall an improvement. At the level of the individual, any value less than 4, which constitutes a 3 or a 2, would classify an individual as a responder. I just want to repeat that on the -- in this -- that a rating of 1 is essentially a cure, and that's not something we're seeking at the moment. So ratings of 2 and 3 are substantial and clinically meaningful improvement at the level of the individual. And again, statistically, we can look at the odds that an individual has shown an improvement as well. So we can look at mean change as a function of the group, and we can look at numbers of cases who respond. And then we can look at the random odds, the statistical probability that an individual demonstrates improvement on drug compared to the odds of an improvement on placebo. So for my final slide, I just wanted to summarize by pointing out that while -- when we do research, we're working with numbers. But these numbers reflect real meaningful change. That the changes that are described by the families, by the physician, can be translated into reliable and valid indices of drug effect. For example, just looking at the first quote here, "She could, for the first time, with activities of daily living like undressing, independently went to the fridge to obtain medicine, it was inconceivable before." If you can recall the anchors we were looking at, it would not be difficult to translate these descriptions. Obviously, 1 would interrogate further and get a deeper understanding of these descriptions, but 1 could translate these descriptions have changed quite readily into objective ratings that no clinician would really disagree with. And in that sense, they're reliable and they're valid. So that concludes my remarks, and I'd like to hand over to Amit.

Thank you, Dr. Jaeger. So to recap, you have now heard from our 2 clinical experts about the continued high unmet medical need in Angelman syndrome, the inadequacy of current treatments available and the use of the Clinical Global Impression Improvement scale as an important and highly relevant outcome measure in assessing individuals with neurodevelopmental conditions. I'd like to take the next few minutes to discuss our OV101 clinical development program, which includes the Phase II adult and adolescent trial in Angelman syndrome known as the STARS study, the design and objectives of the ongoing Phase III study known as NEPTUNE, and the ongoing open-label extension study in Angelman syndrome known as ELARA. So now turning to Slide 45. You can see a thematic of the 3 trials I just mentioned, which together provide core elements of the proposed registrational strategy for OV101 in Angelman syndrome. The STARS trial is our randomized, placebo-controlled, three-arm, Phase II study in adults and adolescents with Angelman syndrome and was completed in 2018. The key takeaways from the STARS study were: one, establishing the 15-milligram once-daily dose as the appropriate dose to move into the Phase III NEPTUNE study; and two, identifying that CGI-I was the appropriate primary endpoint to assess individuals with Angelman syndrome in the Phase III study. We're planning to include the data from the STARS  trial in our registrational submission to support use of OV101 in adolescents and adults with Angelman syndrome. This strategy has already been discussed with the FDA. Now NEPTUNE is an ongoing Phase III study trial and is the first randomized, double-blind, placebo-controlled pivotal study with once-daily OV101 versus placebo in pediatric participants ages 2 to 12 years old with Angelman syndrome. This trial is completely enrolled, and we're expecting data in the fourth quarter of this year. And finally, ELARA is the open-label extension study in Angelman syndrome that is designed to evaluate long-term safety, tolerability and efficacy and is currently ongoing. Initial data from this trial is expected in the first quarter of next year and will include long-term data from STARS, NEPTUNE across these broad age ranges. Moving on to Slide 46. Let me begin with an overview of the STARS Phase II trial first. So STARS was the first industry sponsored study for this condition. Since it was first described in the 1960s, Angelman syndrome has been the condition that has been under study given the high unmet medical need with no currently approved therapies specifically indicated for Angelman syndrome. STARS was an international 12-week randomized, double-blind, placebo-controlled Phase II clinical trial designed to evaluate the safety and tolerability of OV101 in adults and adolescents with Angelman syndrome. Secondary efficacy endpoints were also evaluated and included the overall clinical global function as measured by CGI-I and specific clinical features important for people with Angelman syndrome, including behavior, motor function and sleep. And as we've heard in our previous talk about the clinical features of Angelman syndrome, nearly 100% of individuals with Angelman syndrome have disruption in those domains of behavior, motor, sleep, communications, which makes these areas from a clinical perspective very relevant to evaluate. The STARS study was conducted across 13 clinical sites with the majority 12 centers in the U.S. and 1 in Israel. Many of these sites are considered centers of excellence for treating individuals with Angelman syndrome. Participants were randomized to 1 of 3 different treatment arms. Arm 1 was 15 milligrams of OV101 once-daily at night, so a once-a-day active arm. Arm 2 was 10 milligrams once-a-day in the morning and 15 milligrams at night, so twice-a-day active arm. And the third arm was placebo, so a nonactive study arm. The once-a-day active arm, the results, which I'll describe in a moment, was the dosing regimen selected for the pivotal Phase III study, and we believe this is consistent with finding the appropriate level or range of tonic inhibition as described earlier by Dr. During. So moving to Slide 47. As you heard from Dr. Jaeger, the CGI-I scale is a relevant and optimal measure for assessing clinical effects and progress in individuals with neurodevelopmental conditions like Angelman syndrome. And it informs the impact that syndrome has on affected individuals and their caregivers and families. Recall that the neurologic deficits in Angelman syndrome are global in nature, as the disorder impacts multiple, diverse areas of the brain. And so the CGI-I is a scale that captures the totality of changes that can occur in this neurologic condition in one administered scale. It's also important to note that prior to our STARS trial, there were no regulatory authority endorsed endpoints to assess treatment effect for Angelman syndrome. With the help of Angelman syndrome experts who participated or devised on the OV101 development program, the Clinical Global Impression Improvement or CGI-I scale was deemed the most important and relevant measure that assess individuals with Angelman syndrome holistically or globally, and thus, this became the first prespecified efficacy endpoint in the statistical analysis plan for the STARS Phase II trial. As I mentioned, this trial help identify CGI-I as a clinically meaningful endpoint for Angelman syndrome. On this slide, you can see the impact OV101 given once-daily demonstrated on CGI-I in individuals with Angelman syndrome. First, we observed a statistically significant improvement of 0.79 in the once-daily OV101 arm versus placebo with a p-value of 0.0006 in CGI-I at 12 weeks. This finding, along with supporting evidence on specific areas such as behavior, motor and sleep, helped establish CGI-I as a relevant primary endpoint for the Phase III NEPTUNE trial, which is an important potentially precedent for neurodevelopmental conditions. Additionally, you can see from the graph that we were able to see efficacy across multiple important clinical features in the once-daily dose, with more than 2/3 of responders experiencing clinical improvement in 2 or more clinical features, speaking to the relevance and importance of catching the treatment effect across the global deficits of behavior, motor and sleep that are the classic features of Angelman syndrome. Moving on to Slide 48. You can see that 3x the number of participants in the once-daily treatment arm reported improvement on CGI-I at week 12 compared to the placebo group. This response of once-daily OV101 versus placebo in the STARS study helped to establish this dose as the relevant dose to bring forward into the pivotal Phase III study and also speaks to the relevance of using CGI-I to assess the core clinical features of Angelman syndrome. Moving to Slide 49. As most of you know, the STARS trial met the primary endpoint of safety. We demonstrated that OV101 has a favorable safety profile and was well tolerated across age groups and dosing regimens. This adds to the extensive safety database of this compound, which has previously been studied in more than 4,000 patients and has over 1,000 patient years of safety exposure. The majority of adverse events were mild with a similar incidence across treatment arms. The most frequent adverse events are listed here and include gastrointestinal effects, somnolence or sleepiness and behavioral effects. Achievement discontinuations due to adverse events were low, 1 patient in the placebo arm who discontinued due to irritability. No patients in the once-daily group discontinued and 3 patients in the twice daily group discontinued: one due to myoclonus, one due to seizures, and 1 due to irritability, anxiety and sleep disorder. Moving on to Slide 50. To summarize, the STARS trial achieved its objective of safety and tolerability. We saw a statistically significant improvement in CGI-I at week 12 compared to placebo in the once-daily dose, which has helped establish this measure as a primary endpoint for the NEPTUNE study. OV101 also demonstrated supporting clinical data of improvements across multiple clinical features, including sleep, motor and behavior. As I mentioned upfront, this trial will serve as part of our potential FDA registrational package once the NEPTUNE data is known. Now moving on to the ongoing Phase III NEPTUNE trial on Slide 51. This trial was designed with learnings from STARS and in consultation and agreement with the FDA. It is a one-to-one randomized, placebo-controlled Phase III 12-week trial in pediatric individuals with Angelman syndrome treated with once-daily OV101 versus placebo over 12 weeks. We are using the once-daily treatment regimen from the STARS study adjusted for weight for pediatric agents. At the end of the study, participants can either end treatment or opt to roll into the ELARA open-label extension trial. The NEPTUNE study is meant to enroll 90 participants, ages 4 to 12 years old, with an additional 5 individuals, 2 to 3 years of age, for safety and PK assessments only. The primary endpoint of the trial is CGI-I-AS, which, as we mentioned, can address the heterogeneity of the clinical features of Angelman syndrome. The CGI-I-AS and CGI-S-AS have been refined by developing Angelman syndrome specific objective clinical criteria to serve as benchmarks so that clinicians have, one, consistency in their assessment of study participants; and two, decreased potential inter-rater variability across sites in the trial. Extensive work in refining the CGI-I was done in collaboration with clinical experts in Angelman syndrome and feedback from the FDA Center for Outcomes Assessments Group. Robust training on the refined scales was also instituted at sites from the start of the trial as well as at different time points throughout the trial reinforce this consistent approach to ratings. Investigators use case studies, vignettes with a "gold standard rating" and retraining during the course of the NEPTUNE study to ensure high-quality of assessments. The trial is more than 95% powered for the primary endpoint of CGI-I as well as for the responder analyses. In addition, the study has secondary endpoints being assessed independently of the CGI-I-AS to complement the findings of the primary endpoint. The trial is designed to focus on clinical features for Angelman syndrome that are most important to individuals and caregivers. Sleep measures are being measured by actigraphy measurements and motor communications and behavior clinical features are measured by the Vineland Adaptive Behavior Scale or the VABS. Turning to Slide 52. As most of you know, we're expecting data from the NEPTUNE trial in the fourth quarter of this year, 2020. The key outcomes we are anticipating are: changes in CGI-AS (sic) [ CGI-I-AS ] compared to placebo at week 12; responder analyses and the magnitude of response for OV101 versus placebo; activity and changes in the relevant clinical features of sleep, behavior, motor and communications; safety and tolerability; and we expect these data as favorable to support a path for registrational filings in the U.S., Europe and other global markets. Moving on to Slide 53. You can see the design of the ELARA open-label extension trial. We're anticipating approximately 170 participants in this trial. If favorable, ELARA data would support long-term safety and tolerability of OV101 in individuals with Angelman syndrome, the durability of effect of the clinical changes seen in prior studies with the once-daily dosing regimen, and effectiveness in participants previously treated in the twice daily or placebo arms in the STARS trial. And finally, to Slide 54, a positive readout from the NEPTUNE study would set in motion a comprehensive registrational filing plan for OV101 in Angelman syndrome with the FDA and other health authorities. OV101 has the potential to be the first therapy indicated for individuals with Angelman syndrome. In addition, we have been granted Rare Pediatric Disease Designation by the FDA which may become a voucher, should OV101 be accrued for Angelman syndrome. This is an exciting time for Ovid, but most importantly, for the Angelman syndrome community. And I want to thank the community for their support with the OV101 program, since Ovid first partnered with the community more than 5 years ago. The unmet medical need in Angelman syndrome is high. The opportunity for new therapy to transform medical practices there, and the first Phase III data from OV101 is imminent. So thank you for your time today. I'd now like to hand the call over to Jason Tardio, our Chief Commercial Officer at Ovid, who will give you a brief overview of the commercial opportunity for OV101 in Angelman syndrome.

Thank you, Amit. Throughout the presentation today, we have heard from several experts on topics ranging from the challenges in treating individuals living with Angelman syndrome, the role of tonic inhibition in this disease, the biological rationale for studying OV101 in Angelman syndrome, and finally, an overview of the clinical development program for OV101. To conclude the formal presentation, I would like to take a few minutes to discuss our views on the commercialization of OV101 for Angelman syndrome and how we plan on bringing this important medicine to market. As with everything we do at Ovid Therapeutics, the patients, the families, the caregivers and the communities that we serve will be central to our commercialization strategy. Taking a patient-centric approach to commercialization of OV101 means that we will help to enhance the patient experience by gathering key insights from our patient communities about their journey, understanding their unmet needs and how our medicine might help to address those needs, designing services and support programs alongside our families to ensure that we are providing value and not redundancy and building a go-to-market model that ensures that we are reaching our patients across the globe. And our patients are truly global. Even though Angelman syndrome is defined as a rare disease, affecting approximately 1 in 15,000 individuals worldwide, the aggregate number of potential individuals living with the disease is actually quite large, with estimates suggesting that there are over 500,000 people globally living with Angelman syndrome. So how do we reach all of these 500,000 patients and families? Well, it starts with a proactive approach to engaging with the patient advocacy community, whose support for Ovid and OV101 is essential. Since our inception as a company in 2014, we have been actively partnering with the worldwide Angelman syndrome advocacy community in order to intimately understand the patient ecosystem and their needs. We know the Angelman community and the Angelman community knows us. Today, Ovid is working with nearly 40 different Angelman advocacy groups worldwide on many different initiatives, such as building awareness of the disease, providing educational tools, supporting patient registries, building meaningful programs for family well-being, and designing clinical trials and clinical trial endpoints that are relevant and important to them. We also take the time to listen, to seek to understand what it is like living with Angelman syndrome every day and the impact of the disease. And we know that there is a significant impact of this disease. We have heard from the experts today Angelman syndrome not only impacts the individual living with the disease, causing delayed development, intellectual disability, severe speech impairment, sleep difficulties, seizures and problems with movement and balance, but it also significantly impacts the family and caregivers. Families and caregivers of individuals living with Angelman syndrome report high levels of stress and fatigue, adverse effects on their social life, increased arguments with spouses or partners and increased irritability. Given the complexity and severity of this lifelong condition, there are high unmet clinical needs to help alleviate the impact of Angelman syndrome on both the individual and their families. Unfortunately, there are no currently approved treatments for Angelman syndrome, no current treatments that address the underlying pathophysiology of the disease and no clear guidelines for symptom-based interventions in this population. Current treatments are focused on symptom management and largely limited to improvement of seizures and reduction of sleep disturbances. Given the high burden of Angelman syndrome, new treatments that target the underlying causes of the syndrome that result in improvements in features of the syndrome may be clinically and economically meaningful for patients and their families. We believe that OV101 could help address this unmet need. Through the highly selective activation of extrasynaptic GABAA receptors, OV101 has the potential to restore the deficit in tonic inhibition, which evidence suggests may play a central role in the underlying neuropathophysiology of Angelman syndrome. If approved, OV101 will be the first Angelman syndrome specific therapy with the goal of improving overall functionality in patients. In doing so, OV101 will also lay the foundation for Angelman syndrome specific therapies moving forward. As highlighted on this slide, OV101 is the only product currently in late-stage development for Angelman syndrome. Given this position and its potential as the first to market therapy for Angelman syndrome, we believe that OV101 will become the cornerstone of care for Angelman patients now and in the future, helping to cement Ovid's leadership position in this category. Given the high unmet need associated with this disease, the global commercial strategy for OV101 in Angelman syndrome is laser-focused on ensuring that, once we have positive Phase III data and subsequent regulatory approvals, we're able to accelerate access to this important medication to as many appropriate Angelman syndrome individuals as quickly as possible. We plan to accomplish this outside the United States through a series of regional strategic partnerships with innovative, specialized, rare disease biopharma companies to leverage their deep regional knowledge, their established infrastructure, their understanding of the local regulatory and market access landscapes and their blueprint for local launch success. In July, we executed the first of these types of collaborations with Angelini Pharma, which obtained the exclusive rights to OV101 for the potential treatment of Angelman syndrome in the European Union, United Kingdom, Switzerland, Turkey, Russia and other countries in the European Economic Area. In the United States, Ovid Therapeutics is planning on commercializing OV101 alone, and we are in the process of building out the commercial organization in preparation of this milestone. To prepare for a global launch of OV101, Ovid Therapeutics will be launching a broad disease data awareness campaign in 2021, with the goal of elevating awareness of the signs and symptoms of the disease and improving accurate diagnosis as up to 50% of individuals with Angelman syndrome are originally misdiagnosed. Additionally, in conjunction with the patient advocacy community, we have plans to roll out a free of charge, no cost genetic testing program to help alleviate one of the key barriers to confirmatory diagnosis. We look forward to sharing more information about these important programs in future calls. In conclusion, Ovid will embark upon a patient-centric approach to commercializing OV101 to ensure that we are meeting the needs of the vast global Angelman syndrome community of over 500,000 potential patients. There are significant needs in the area of motor functioning, communication, behavior and sleep for individuals with AS and their families that are not addressed by symptom-based interventions, given their limited utility. If approved, OV101 would be the first Angelman syndrome specific treatment that appears to modulate tonic inhibition, an important component of the pathophysiology of Angelman syndrome. OV101 will benefit from first-mover advantage and will lay the foundation for AS specific therapies now and in the future. Ovid Therapeutics is actively preparing for a successful global launch of OV101 and will be executing a broad disease state awareness program beginning in 2021. Thank you for your time today. Before we go to Q&A, we would like to share with you a short video about a family's journey with Angelman syndrome. [Presentation]

Wow. Thank you. What a very powerful video. We're honored to have analysts and investors with us today at our seminar, but we are also honored deeply to have many patients and caregivers who expressed a strong desire to be part of today. And so we share this with deep gratitude to them. And what I'd like to do now is to turn the call over to Amit to moderate the Q&A. Amit, over to you.

Great. Thanks, Jeremy, and thank you to all our presenters today who hopefully have provided you a really comprehensive overview about Angelman syndrome and our OV101 development program at Ovid. So I'd like to first start off the Q&A session with a few questions for our experts just to kick off. And maybe I can start with Dr. Keary. Chris, tell us if NEPTUNE shows a result that is positive, what does that mean to you for clinical practice for Angelman syndrome?

Yes. Thank you, Amit, and thanks for the opportunity to talk today. If it turns out to have these favorable results, then we are looking at something that would be the first potential treatment for the core pathophysiology of Angelman syndrome. And that's a huge thing for any clinician because it means that, for the first time, we have treatment options that we can offer that are to address the core of Angelman syndrome itself. It also means that this would be the start of a move towards being able to prescribe this medicine. And I know that after essentially the whole time of caring for patients with Angelman syndrome, not having something to say, look, this is something for the core treatments of it itself, it's extremely exciting for clinicians. It's something that families have been waiting for, for a long time. When I was at the last Angelman Syndrome Foundation, meeting a lot of families are excited to have researchers looking at actual treatments. And there's an energized sense in the air of there being treatments down the line. And so there's a lot of hope around it. So I think it would be extraordinarily impactful. The fact that there is favorable evidence in not just kids but also adolescents and adults from the STARS trial also indicates that these are treatments that could be also potentially helpful for not just kids but adults, which is also very impactful. So it would be a major change in the world in Angelman syndrome.

That's great. And maybe just 1 follow-up question, Chris. You mentioned a bit about your clinical practice and the impact different changes can have -- the major impact of different changes can have. What -- do you -- and we spoke about the CGI-I as a primary endpoint measure in our Phase III NEPTUNE study. What does the point improvement look like at the patient level, at an individual person level or a family level?

Right. Right. As a psychiatrist by training myself, I'm used to seeing the CGI-I used, as Dr. Jaeger talked about in her presentation, in different studies of conditions such as bipolar disorders, schizophrenia. So I have a lot of familiarity with it from my own training and can say I think about it as being a tool that measures meaningfulness, measures the meaningfulness impact of a treatment as judged by the rater on the person you're seeing, the subject. And so 1 point change is an additional level of clinical meaningfulness. That may be a small number, 1, but it refers to a step-up in terms of the level of meaningfulness. It is essentially a measure of meaningfulness itself. So that could be a lot of different manifestations. That could be, for instance, an individual Angelman syndrome that goes from speaking 2 words at the beginning of a trial to speaking 5 words. It could be an individual that could just go upstairs, but not go downstairs, without help, to now able to go downstairs independently with minimal assistance. That it could be a variety of different things, but it's measured and its impact on the family. So you're essentially automatically saying off the bat 1 point difference is more impact, more difference in the patient's life. And this is -- differs significantly.

Yes. No, that's very helpful. And I think as you mentioned, the point improvements can have a massive difference in the lives of individuals and families. And Dr. Jaeger, do you -- can you expand a bit more about what you said, I think, in your presentation about the CGI-S and the CGI-I, very, very helpful? How should we think about that point improvement in the CGI-I score as you see it, and as we look about -- as you look at the improvement we saw in the STARS study and as we look forward to the NEPTUNE trial?

Yes, right. So a common challenge for people to understand these kinds of data are you look at a number that's some sort of interval. Obviously, for a single patient, the movement has to be a single whole point. And in STARS, you had essentially a 0.79 difference between the placebo and the drug. Well, what's a 0.79? Well, there are lots of ways to get a 0.79 average but what it means is that you had many more people moving 1 or 2 points in the direction of improvement on drug than on placebo. And you can look at the odds at the level of the individual, right? So that number translated to an odds ratio of something like 3. So you have a threefold chance, improved chance of seeing -- or greater chance of seeing an improvement on drug than on placebo. I have to tell you these effect sizes are just stunning. I mean we don't see effect sizes this big in most area of neuroscience and psychiatry.

Thanks for that, Judith. I think that point about the 0.79 you've got the -- when you're looking at a population is different than an individual level where you'll have 1 point changes like in a level changes. So no, that's helpful. And we're looking forward to data from NEPTUNE coming soon. But with that, let's open up the line to the audience. And I do know we've received multiple questions from our families of individuals with Angelman syndrome on the line. And hopefully, we'll be addressing most of your questions. But if we don't get to them, we will find a way to address those through the advocacy organizations and make sure that those questions are answered. So with that, let's open the line to the audience, and I'll turn it back over to the operator.

[Operator Instructions] Our first question comes from Charles Duncan of Cantor.

Thank you, Jeremy, and team for hosting this call, and it has been very helpful. So thank you to the 2 KOLs that spoke as well. I had a quick question regarding phenotypic heterogeneity in adults and adolescents versus in younger people, pediatric people. I guess I'm wondering if you think that heterogeneity is greater or less in the older patient population given rapidly changing albeit compromised neurodevelopment in the pediatric population? And how do you think that, that may impact your ability to interpret the results from NEPTUNE? And I have 1 follow-up.

Great. Thanks, Charles, for the question. Yes. I'll just start off, and I'm turning to Chris after this. We've never -- we think about Angelman syndrome as a nondegenerative condition, so that there is this plateau of development. And as we've seen before and mentioned before that a 5-year old with Angelman syndrome often has very similar features as a 15-year-old or a 35-year-old with Angelman syndrome. And so that's why when we look at our STARS program in adults and adolescents, we've complemented that with the NEPTUNE study, which is more in pediatrics to really address a wide range of ages, with clinical features that are very similar across agents. But with that kind of background, maybe, Chris, you could actually -- in your practice, what are your thoughts about this?

Sure. It's a great question. I think that a lot of the gains that are made for kids in Angelman syndrome with things like physical therapy and speech therapy are oftentimes hard one over a period of years. So sometimes you don't know when a child as young as 4 or 5 years old with Angelman syndrome, what they're going to be capable of. And you have a little bit more of a sense by the time you get to the teenage years, how there might have been differentiations in terms of those areas where there's the most heterogeneity, which tend to be like motor movements, how much speech gets developed, how much of a problem sleep may be. We know that going into adulthood, that's when there can be worsening in a lot of issues like behaviors, particularly things like aggression or anxiety or hyperactivity can change into the adult years. So that can result in more heterogeneity among adults than in young, young kids, I'd say probably more likely to be prepubescent kids rather than teens. But then in the early pre teen years, there can be really differences in terms of severity of seizures, where by the time you get to sort of the adult years, many patients have had their seizures stabilized. So there can be significant heterogeneity, even in the younger years as well. It's one of the major challenges in terms of designing outcome measures and part of the reason why the CGI is such a nice choice.

Yes. Got it. So that's helpful. I had just 1 additional question for you, and that was -- I think company mentioned that sometimes these patients are misdiagnosed. And I'm just kind of wondering what they are misdiagnosed with. And if you would see activity or good efficacy out of the NEPTUNE study as perhaps having predictive value for other neurodevelopmental disorders that share similar symptom complex such as perhaps even Fragile X or others that you could mention? And then will you be looking at CGI point changes? Or will you be looking at some kind of responder analysis or, call it, an odds ratio to try to communicate with your caregivers and patients as to whether or not they may respond to the drug?

Sure. I think in regards to the first part of the question that you asked, I think that it is true that many patients with Angelman syndrome can be misdiagnosed, but that is less and less common these days. Back around the beginnings of the identification of the diagnosis of Angelman syndrome, a lot of the times a clinical basis was used to make the diagnosis before the genetic testing was even done. It is much less likely these days for there to be misdiagnoses. And what could be misdiagnosed? Well, it could be misdiagnosed with just let's call idiopathic or just regular intellectual disability without a known genetic basis behind it. That was -- that's probably in my experience the thing that I've seen mischaracterized the most. And I guess another possibility be Rett syndrome. But 1 of the things that's unique about Angelman syndrome is people with Angelman syndrome tend to be highly social. And so it's less likely to be mistakenly called autism, for instance. I think it's an open interesting question about whether or not OV101 might be -- might have reason to think that it could help distinguish other neurodevelopmental disorders or whether it might have efficacy in other neurodevelopmental disorders. I think it's an interesting question. I think just the way that Dr. Jaeger talked about the odds, for instance, of being a responder, I think the discussions of the odds of being a responder is judged by a CGI-I of 2 or 3. I think that's a helpful way to talk with families about it. And there's a lot from the STARS trial that you can talk about that in terms of the odds of being a responder, which I think will resonate with families in how to think about how useful it could be.

So Chris, maybe -- Judy, I think you had a comment about -- thanks, Charles. And Judy, if you want to comment about that odds ratio, I think you had talked about that a little bit as well.

Yes, I wanted to make a distinction, as I mean, Chris, has it spot on. But the distinction between the endpoint as used by [ regulator ] for approving a drug the way in which we communicate, and that's why you will sometimes hear us use different innovative measure. So for regulators, we do typically use a number like the percent of change or the absolute amount of change or a standardized distal effect size. And [indiscernible] are often the way you then communicate effects like this to individuals because for an individual what does it mean to me 0.79 [indiscernible]. But the odds ratio tells me something about the risk and benefit of the drug that I may want to try. So I just wanted to point that out. That's a distinction that's important to understand.

Thanks for that Judy. Great. And thanks, Charles, for the question. Next one?

Our next question comes from Ritu Baral at Cowen.

Forgive me if I missed this, but could you go into a little more detail as to how on sort of a technical basis the CGI assessment changed between the Phase II and the Phase III? Were the same sort of methodology of prompting used between -- on the different subscale?

Yes. Thanks, Ritu. And I'll turn to Judy for that response. I'll just mention briefly that the CGI-I-AS is that we're using the CGI-I-AS in the NEPTUNE study. Has been -- I think what we've added are very specific clinical objective criteria that everybody who's the raters can use across the relevant domains of motor, behavior, communications and sleep. And so we've -- the additional points -- these objective clinical criteria are specific for people with Angelman syndrome. And those examples that Judy has shown in her slides are really reflective of people with Angelman syndrome, for example, using hand over hands for utensils versus something different. But Judy, did you want to touch base on, as you were highly involved in this effort?

Yes, sure. So I mean, the endpoint is the same because the primary endpoint for this trial is the global improvement score. But of course, the methodology evolved to improve the reliability and validity of the scale, to improve the level of agreement between raters, there were methodologic improvements made with respect to how the interview lens and how the subdomains were grouped in the CGI-S component. But the CGI and the CGI-I, and this was at the advice of regulators. Rather than recording change per domain, we now record global change, but the global change is, of course, the same. So we're applying it somewhat differently but the examination and the endpoint are essentially the same as they were -- as it was for STARS.

Got it. And who are the sources of the clinicians assessment? I think you mentioned that I think parents are pretty universally pulled by the investigator, but you mentioned speech pathologists. Like what's the usual gamut and does it vary significantly patient to patient?

I actually think Chris is better positioned to answer that than I as he's doing these interviews.

Sure. Yes. I can jump in on this one. It's -- of course, an interview with the parent is a key part of that evaluation, and that's why it's important to have it be the consistent, same caregiver or parent they are interviewing for each time. But evaluators are also encouraged to ask probing follow-up questions in their conducting of the CGI-I to really feel confident in the choice that they are making. Part of the training for evaluators for the study is that it is not just a parent scored instrument, that it's a clinician scored instrument and clinicians have to use their judgment in terms of asking follow-up questions, really feeling convinced about the score that they are providing and to also document their rationale, the things that they saw change, that's the rationale behind that change, so they can reference that for subsequent follow up visits. And then the other piece of data that's important is that needs to be a visual component where you see the subject, where you can ask probing questions based on what you're seeing the subjects do when you're conducting the CGI-I. So there's a visual interact component to it as well.

So Ritu, I think there is -- the criteria we said are objective clinical features. So there's consistency across, but it is a clinician rate of scale. So the principal investigator is the one who's making that assessment. And taking in that input from the care -- primary caregiver, usually one of the parents -- or the board of primary caregiver and then the relevant information. And most of the centers we're using are centers of excellence. So there is a team of people. So that's the principal investigator that's responsible for that assessment.

Got it. That's helpful. And -- oh go ahead.

I was going to say if anybody is on the line and who's not speaking, could they go on mute? And especially if you're using the webcast as well as a call-in, there's a little bit of an echo on the line. Thanks.

And just one tiny little additional follow-up. That patient-level data, that detailed scores, have you communicated with FDA about how interested they might be in seeing that granular data as part of the review?

So we're going to await for the data in NEPTUNE, and then we will have kind of further updates about those interactions after the data. But yes, thanks for the question.

Our next question, Brian Abrahams from RBC Capital Markets.

I guess for Dr. Keary and Jaeger. I'm curious in light of the varied deficits that are seen in this disease, are there any domains that may be more or less important to you or secondary end points that you might be focusing on when the data become available? And maybe as a corollary to that, it sounds like small changes should be able to be picked up by CGI-I, but I'm curious if there are positive trends in the study that don't quite reach statistical significance. Do you think this is still something that the academic and patient community would push for availability of? And maybe for the company, where do you think regulators might stand in that regard?

Thanks, Brian. And again, if I can remind people to go on mute, if they could. And Chris, do you want to start off and then Judy?

Absolutely. The first part of the question that you'd asked in particular, I had a thought on -- if you could just remind me again the first part of your question because I was off to thinking about the regulators.

Any domains you've been to.

Yes. Thank you. Exactly. So in my mind, any change in any of these domains would be highly impactful for families. When the CGI-I was developed with input from families and input from clinicians who had expertise in Angelman syndrome, these particular domains that made up the CGI-I, which were used as anchors, were the ones that were among the most important to families. So one of the ones that's consistently rated the highest for families are speech, but things that have resulted in an improvement in motor function or improvements in sleep or improvements in behavior would still be highly impactful for families. And there are challenges for which I don't have a lot of treatments available and feel frustrated when I'm trying to care for patients. So while I think...

And I think, Judy -- go ahead. I was going to say and then, Judy, I think you're actually involved in that actual -- these different domains. When we looked at trying to pull together the CGI-I and the relevant domain, they all had, like you said, Chris, frustration in terms of treating the behavior or motor or speed to communication, but it is different among individuals, right, at the level -- and that's why we looked at this as a global CGI score.

That's right.

Yes. There's another interesting thing that I learned from these interviews that was kind of an epiphany for me, which is the nature of the interaction among the domains, where I'm learning about an improvement in fine motor results in an improvement in the ability to use a touch screen assistive device, therefore -- thereby improving communication so they can say what they want. They can convey their desires, thereby improving overall behavior because there is less frustration. So you have an improvement in fine motor that translates to better communication and better behavior in children. So that's why the CGI-I is so powerful because you could -- you would technically have an improvement in one domain that's cascading into the other, and you can measure the overall.

Great. Yes. Thanks, Judy. Thanks for that. Great. Shall we move on? Brian, does that address your question?

Yes. And then I guess, just kind of the idea of positive trends that don't quite reach statistical significance. Just I guess interpreting the clinical meaningfulness of those and whether or not that's something that, in conjunction with the STARS study, the company would potentially look for approval of and whether the KOLs believe that's something academic and the patient community would push for.

Yes. Maybe I'll take that. I think like -- I think we -- Judy talked about the CGI-I. Any movement into CGI-I, so if you're looking for a study for the NEPTUNE study data readout, in movement in CGI-I, by definition, means it's clinically meaningful. So that point about the clinical meaningfulness is that if you have a movement that's statistically significant with NEPTUNE, as you've seen with STARS, that would be clinically meaningful. And the secondary end point that I described in the design of the study are meant to inform what's changing in the CGI-I because the point different by itself doesn't tell you much, but -- so we have to dig a bit deeper into the various clinical features, whether it's behavior mode or speed on what's changing because that's what will help inform what's changing within the CGI-I. So that's where those secondaries come in. But I think we'll see very soon in -- when we have the data in NEPTUNE and then can inform about the next steps. But that's what we discuss upfront with the regulators.

[Operator Instructions] Our next session comes from Tim Lugo of William Blair.

I'm sorry but I'm required to ask another CGI question. Dr. Jaeger, I believe you mentioned that the 0.79 effect, you described as large. And when we really drill down into the anchors, especially the motor improvement anchors, I can kind of understand that now. I think you described walking with one hand support as a 4 but maybe running well with minor gait issues as a 2. I mean that seems like a -- kind of a massive improvement. But also, what are your thoughts about maybe that is almost too high of a bar for a 2-point improvement? To me, it seems like a major step-up. And I guess were there actually -- and maybe for Amit, were there actually patients in STARS that did make such a major step-up but weren't really captured with the kind of legacy CGI tool?

Yes. So I think -- go ahead, Judy, and I can answer that second part.

Sorry, okay. So actually, you're quite right that a 1-point improvement in a single domain is substantial and a 1-point -- a 2-point improvement in a single domain is massive. That is to say the movement from a 4 to a 3 or the 4 to a 2. And indeed, this is a course instrument. Now those -- the example I gave was motor-only. Recall that the primary end point for this trial is the global, which means that if you saw that on motor-only and there was no further consequence and any other feature -- clinical feature, it might not even warrant a 3. So you need to be seeing a cascading of effects that affects the life of the individual before it would warrant a 3 on the global. So you're absolutely right this is a very course measure and a 1-point change is very real. And if you're looking at odds of change of 1 point, you're talking about odds of somebody responding meaningfully to the drug.

Yes. And I think we've seen that within STARS as well. When you look at that, Tim, that we see people with those level changes. And the 0.79 comes from when you look at a group effect, right, because there are some people who didn't change and then some people who had 1 versus 2. Some people had no change. And then your group population statistics gives you that decimal point change. But individually, you're seeing people who are changing at least 1 or 2 because that's how the scale is administered.

Okay. And maybe the quick follow-up, talking about the interconnection of all the domains. It -- maybe I'm just projecting, but I know my behavior tends to improve when my sleep improves. Is this something that is kind of -- what domains are more highly correlated in their changes? Or is it kind of equal among motor, behavior, sleep, all it's measured?

Yes. So I just mentioned, I think it goes back a bit to how the CGI-I is administered because we don't have a disease-specific scale that Judy mentioned because of the weighting problems, right, because the weighting of different symptoms or some features might be problematic. And so the CGI-I is looking at this holistically. And I think the other point I think both Chris and Judy made were about -- you have -- fine motor improvement in using utensils may improve your ability to use a communication device, which may translate to communication. And so you may have this effect that's captured regularly by the CGI-I. And so when we are looking at when -- the design of the study, there's no weighting specifically for the different features that we are also assessing independently with the CGI-I. So the secondary includes sleep via actigraphy and then the Vineland Scale, which are independent scales that have been used for those to clinical features.

I'm showing no further questions at this time. I'd like to turn the call back over to Jeremy for any closing remarks.

I think actually, there's Michael Higgins. Please, Mike, are you there?

[Operator Instructions]

Can you hear me, guys?

You bet.

Yes.

Great. Sorry. Just dropped the line for the wrong time there. I appreciate you getting me back in here. Very helpful, very informative. I was hoping to hear -- or just to clarify and this is a follow-up from the STARS KOL event that was hosted a year or so back if we have yet all of the components of the CGI to review. And I was just looking at the slide here. Slide 40 gives us fine motor, gross motor as examples within the CGI. Do we have all of those? I thought maybe there was 9 parts to the CGI components. And we talked about this a bit in the past, Jeremy. So if you can help me out as to what components are all involved with this.

So let me hand over to Amit. And he can walk you through that slide again if that's okay with you.

Yes.

Or actually, Judy, please, go ahead. Yes, sorry. You guys take -- if you want to dive in.

So Mike, the CGI, the 9 domains in STARS was before we had adjusted the CGI for Angelman-syndrome-specific features. So the NEPTUNE study breaks down the CGI questions, the features of behavior, motor, sleep, communication. Those are relatively the same domains that were used in the STARS study, they were broken down a bit more by anxiety, irritability, for example. That would be part of our current NEPTUNE study, the behavior domain. So it's very similar to the STARS. So Judy, did you want to comment on that? Because I think this was one of the areas we try to consolidate to make it a bit easier to address and assess the CGI-I.

Yes, yes. So just -- because this is related to a previous question. So the CGI-I is the same and the domains that were covered are the same, but what we're calling them and how we're activating them is simplified. So motor, we have fine and gross. And then we had a range of 2 different behavioral science categories, whereas we've now collapsed these based upon further investigation of meaningfulness. But fundamentally, the same material is in there and the CGI-I reflects the aggregate, biggest fault. So yes, there were 9, and now there were 4, but the 4 subsumed the 9, if that helped.

That does considerably. Okay. I'll take a look again at STARS. And then one follow-up, if I could. I'm not sure if you can clarify this to a complete degree, maybe more so for Jeremy's. In Europe, if we look ahead there, what trials may or may not be needed going forward to file, assuming you have positive results here? Do you think you can file on that? Where are you with the European regulators?

So first of all, I'm delighted to be working with Angelini, great partner to have. It involved something that the [indiscernible] Europe. So we -- a little bit difficult to speculate right now until we see the results. They -- with our partner, Angelini, we will work with them definitely, and we've not provided any timing. So we'll just work in parallel for the moment. I think the NDA will be the basis of their MAA. Amit, do you want to add anything to that?

Yes. I think you summarized it. I think we're working very closely with Angelini. We are awaiting the NEPTUNE data. We'll have interactions with the European regulators, the CHMP and abide the next steps. But the data from STARS, NEPTUNE and ELARA will form a core part of that data package. And then we'll work as closely in parallel and as quickly as possible with Angelini supporting that effort as well. And then we'll have more information once the data from NEPTUNE is down.

And then Mike, just to add to that. This is a global topic. This is something which we want to get around the world and we want to -- we're planning for rest of world regulatory submissions, but it's premature to really go into detail on this. And the NDA is definitely going to be our first priority. Remember there are -- we estimate over 500,000 individuals around the world who will need this medicine if it's approved and we want to give it to them all.

Thank you. I'm showing no further questions at this time. I'd like to turn the call back over to Jeremy for any closing remarks.

Thank you very much. And first of all, my thanks to Amit, Chris and, of course, Judy and the team. Thanks a lot for your presentations. I also want to extend my thanks to investors who have taken time to come here. It's a long day. We hope this has given you a really fundamental look at Angelman. This is, after all, the first time this has ever been done for investors. I want to -- and this is an opportunity for you to think through and take a look at what's coming up in the future. We're really excited by the opportunity to display the data from NEPTUNE. And then I want to also take the opportunity, thank you -- to thank the various other parties who've joined us. We know there's a tremendous amount of interest out there in the community. It's because of you that we've been doing this. We are very closely aligned with you, and we greatly, greatly appreciate your support. As you know, Ovid will always take care of patients. And thank you so much, everybody.

Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. You may all disconnect. Have a great day.