Study Update

Feb 4, 2021

Good afternoon and welcome to the CELINO Key Opinion Leader meeting on DCCR for the treatment of Crater Willi Syndrome. At this time, all participants are in a listen only mode. A question and answer session will follow the formal presentations. If you would like to submit a question, please use the Q and A function at the bottom of your Zoom app. As a reminder, this meeting is being recorded and a replay will be made available on the CELENA website following the conclusion of the event. I would now like to turn the call over to your host, Doctor. Anish Bhatangarh, Chief Executive Officer of Saleno Therapeutics. Please go ahead, Doctor. Thank you, Sarah, and welcome everyone to our KOL event today. I'm Anish Bhatnagar, CEO of Seleno Therapeutics. I'm joined by Jim MacInnes from the company. He's our CFO. I want to point you to our forward looking statements slide. I would encourage you to review our latest filings with the SEC, including the 10 ks and the 10 Q filings. We're also joined today by 2 key opinion leaders, Doctor. Jennifer Miller from the University of Florida and Doctor. Theresa Strong from the Foundation for Productivity Research. The agenda for today is going to be Doctor. Miller speaking about PWS and the unmet need, followed by Doctor. Strong, who will talk about FPWR's survey on the impact of COVID. I will follow that with a conversation about the impact of COVID on the destiny of PWS data. And Doctor. Miller will come back to speak about her experiences in 601 and 602 patients with DCCR. And finally, Jim MacInnes will talk about our initial thoughts on the commercial potential for DCCR. So without further ado, I will pass it on to Doctor. Miller. Doctor. Miller? Thank you so much. So, as was mentioned, I'm going to talk about just general about Prader Willi syndrome to start with. And I love this picture because I don't know if you can see their shirts, but they say, You think you're hungry? Try having Prader Willi Syndrome. If you can go to the next slide, please. So Prader Willi Syndrome is a genetic condition that's caused by the lack of paternal contribution of chromosome 15 of the area of Q11.2 through Q13. And the prevalence of Prader Willi syndrome is about 1 in 15,000 to 1 in 30,000 live births. Prader Willi syndrome manifests even in utero as decreased fetal movements, often polyhydramniosudent, impaired suck and swallow. And then typically, when babies with protobelia are born, they're about 15% smaller for both weight and length than their unaffected siblings. The average age of diagnosis today is about 1.2 months of age, and this is largely due to parent advocacy groups like the Foundation For Prader Willi Research and the Prader Willi Syndrome Association that have done an excellent job of educating doctors to be more aware of the syndrome and to do testing early. Next slide, please. There are 3 different ways that Prader Willi syndrome typically happens. The most common is a deletion of that area of chromosome 15 in the Q11 through 13 region. This is a random event that happens during spermatogenesis. The second most common way is something called uniparental disomy, which occurs in about 20%, 25% of individuals with Prader Willi syndrome and is due to having 2 of mom's chromosome 15 and none of dads. And this is actually a trisomy rescue that occurs due to a problem during oogenesis. And lastly, the most the least common way is something called imprinting defect. And this is something again that happens to aspermatogenesis when dad fails to put the paternal imprint on the chromosome 15 that he's passing on in his sperm. Next slide, please. Prader Willi syndrome has some fairly unique phenotypic features. As babies, the individuals with Prader Willi don't want to eat. They will actually close their mouth, they'll tongue out the bottle, they'll turn their head away. So you have to basically force feed them in order to keep them alive. So this will involve something like a nasal gastric tube, sometimes surgically implanting a gastrostomy tube, or in some countries, it just involves cutting the bottle nipple and simply pouring formula down the throat to keep the child alive. And despite all these measures, there is a fair proportion of these individuals that will have failure to thrive despite adequate calories in infancy. And then this is followed by a period of relative normalcy and weight gain and appetite and then followed again at around 15 to 36 months of age by weight gain. And this weight gain is not associated with either an increased appetite, increased food intake, increased interest in food. It's just weight gain in and of itself, and it precedes the changes in appetite, which is very unique. Individuals with Prader Willi syndrome all have low tone. It's most commonly noted in infancy and most severe in infancy, but it does persist throughout the entire life due to decreased lean muscle mass compared to fat mass. They all have speech and language impairment and require therapy for this. This often also causes problems with food intake because they will often just shove food in their mouth because they don't have normal sensation or tongue movement in their mouth. And then they have a bunch of endocrinopathies that are due to hypothalamic pituitary dysfunction, which is why I follow individuals with Prader Willi syndrome. There is, in today's world, a huge variability in the cognitive impairment that is associated with this syndrome, but they all have very characteristic behaviors. There's a lot of OCD and anxiety behaviors, rigid black and white thinking, repetitive behaviors, and there can be psychiatric issues that occur later in life. Next slide. So this is the nutritional phases that I alluded to in the past slide about how their eating changes over time. So when they're infants, as I said in Phase 1a, they have difficulty feeding and require assisted feeding and then the phase where that normalizes is called nutritional Phase 1b and that typically occurs between 6 9 months of age. And that phase is associated again with normal eating and basically normal weight gain. But physiologically, biochemically, what's happening in these individuals is because of the malformation of the hypothalamus and the hypothalamic dysfunction, there is a central resistance to insulin that results in increased hepatic glucose output and insulin secretion in the periphery, despite the fact that on the surface you're not seeing any signs of hyperinsulinism. This is followed, as I said, at around 15 to 36 months of age by nutritional Phase 2a. And nutritional Phase 2a, again, is weight gain without a change in insulin is anabolic, it causes weight gain, but it causes fat weight gain. Insulin is anabolic, it causes weight gain, but it causes fat weight gain. So we believe that this postprandial hyperinsulinism is actually what's causing this weight gain that's not associated with a change in anything else. And this is then followed at around 4 or 5 years of age by what we call nutritional Phase 2b. B nutritional phase 2 B is an increased interest and awareness of food. So this is when they become a little bit more anxious about food. They talk about food a lot more again, individuals with probably a very routine driven. So this is when they can actually tell time very early for their age, because they're very dependent on a schedule and routine for their feeding. And again, biochemically, what's happening during this phase is that that insulin as well as leptin resistance. And when there's leptin resistance, at the level of the blood brain barrier, you begin to get more hungry because you don't get that signal of, say, tidy and having enough body fat that gets through to the brain adequately. And with time, these biochemical changes result in what we call nutritional phase 3, which is the classic phase of Prader Willi associated with profound hyperphagia, which is just simply a really increased appetite. They don't feel full ever. And so, because of this lack of feeling full, they of course then have worsened weight gain, and their body composition is already abnormal. It can become more abnormal with even worse increased fat mass and lower lean body muscle mass and the leptin resistance and decreased insulin sensitivity also become worse. Next slide, please. This is a growth chart that sort of shows that these next two slides will show you the natural history of Prader Willi if left on attended. So this growth chart was actually pre growth hormone. So you can see that the height is actually pretty low. Nowadays, we start growth hormone at diagnosis. So typically in infancy and the height is better than this. But what I want to show you on this growth chart particularly is the weight trajectory. So what you can see on this growth chart is that at the beginning up until about 4 NG tube was removed, and the weight was tracking along fine. And then when the NG tube was removed, there was some significant failure to thrive that occurred. Weight became more normal again at around 18 months of age. And then you can see here at 28 months of age was when they entered nutritional Phase 2a and the weight began to increase exponentially despite no changes in appetite or fullness. Next slide, please. And this is what happens again in the natural history if left unabated. So you can see here that this individual went into nutritional Phase 2b at around 4 years of age where the weight went up even more. And then subsequently over time, the weight continues to just go up unabated if the food is not locked up and there's not environmental controls. And in this particular person, it exceeded the height chart because it was so significant. Next slide, please. So the body composition of Prader Willi, as I've mentioned, is abnormal from the get go. They have increased body fat and excess body fat compared to muscle mass. Their overall body fat as well as their overall subcutaneous body fat is higher than BMI match controls, but their visceral fat is actually a little bit lower. They do again have decreased muscle mass compared to BMI match controls. And because of having more fat and less muscle this contributes to a more sedentary lifestyle because exercise is more difficult. Next slide. The behavioral problems in Prader Willi, again, are fairly characteristic among individuals. Hyperphagia occurs in virtually everyone with this syndrome at some point in their life. Again, the most average age of diagnosis for hyperphagia is around 8 to 9 years of age, but it can occur later than that as well. Some individuals don't hit hyperphagia until their late teens or young adults. And hyperphagia is really, again, it's just constantly thinking about food, trying to find a way to get food. They often will have tantrums and meltdowns, particularly over food, but not always. Again, when you're hungry, you're irritable. And so they often will have tantrums and meltdowns over little things just because they're more irritable because they're really hungry. They do have, as I mentioned, some characteristic obsessive compulsive behaviors, things like hoarding things, ordering and arranging things, but they also can have some self injurious behaviors like skin picking, which are fairly common. And we think that these compulsive behaviors are in a response to anxiety, which is almost ubiquitous in the population. And this anxiety is both food related and non food related. And as I mentioned earlier, there's a lot of rigid thinking, a lot of repetitive questioning that is manifestations of the anxiety. And all these things that I've described, as you can imagine, sort of cross over into the autism spectrum realm, in that kids with autism behaviors with autism have these similar behaviors of hoarding things, ordering and arranging anxiety, that kind of stuff. And so almost anyone with probability could be classified on the autism spectrum just based on behaviors alone. And unfortunately, one of the problems with this syndrome, one of the bigger problems with this syndrome is aggressive behavior. So because these individuals are starvingly hungry, they can be very aggressive, particularly when it comes to food. They'll go after their parents or anyone else who's trying to protect them from eating themselves to death by protecting the food from the individual. And often it's the mothers that they go after because they perceive them as a weaker link, and they will actually physically hurt their mothers or other family members who are trying to keep them away from food. Next slide, please. There is, as I mentioned, a huge variability in cognitive impairment in this syndrome. Typically, in today's world, it's mild to moderate cognitive impairment. There is intellectual delay in learning problems that can exist, but these can be overcome academically with parenting and with the teachers and tutors and things like that and a lot of repetition and work. The major problem actually for most of these individuals is the cognitive rigidity because this leads to behavioral problems. So for example, when these individuals are in school and the teacher says, we're going to do math before we do reading, if the individual with probability is not done with their math and the teacher tries to transition on to the next subject, there's going to be a meltdown because they were told they're going to do math before they're going to do reading. And so that cognitive rigidity often hungry. Again, the more hungry you are, the more irritable you are. And so we definitely see that as hyperphagia begins and worsens, cognitive rigidity does become significantly worse. And population. And this also, of course, worsens both food behaviors because tired and hungry are very closely tied together in the brain. And it also, of course, worsens cognitive rigidity as well, because the more tired you are, the more easily you're angered or set off. Next slide. The burden of care for families with Prader Willi, I think, is greatest in infancy and then in adolescence and young adulthood. Infancy just simply because that's when they get the diagnosis, there's a lot of therapies and doctors appointments and such like that, but then it becomes a little bit easier for a while until hyperphagia hits. And when that happens, that's when things really get rough for families. It puts a big strain on family relationships of all sorts. And there have been studies that show that the siblings of individuals with Prader Willi Syndrome will have some PTSD symptoms, behavioral problems, a lot of eating disorders in the siblings because food is such a major focus for the family because of the individual with Prader Lease syndrome. And the caregivers often report reduced sleep quality, anxiety and depression. And this makes sense. These individuals, when they become hyperphagic, they have to be watched 20 fourseven. They cannot be left unobserved. And so because they'll get up at night when everyone's asleep and they'll go looking to see is anything unlocked or they'll leave the home to try to get to food. And so as a result, they are often locked in their room. You know, everything in the kitchen is Often, families have to have cameras that are motion activated so that they know when the child was Often, families have to have cameras that are motion activated so that they know when the child with potter willy is moving around the house to try to look for food. And unfortunately, the divorce rate in this syndrome is even higher than it is with other developmental disabilities. It approaches 80%, and that is because this is a very complicated syndrome that involves every aspect of the individual and their family's life. And so, of course, the whole thing adversely affects work and economic opportunities for the family because, again, someone has to be there watching this kid 20 fourseven. Next slide. As I mentioned, the burden of this is huge on families, and the appetite is, of course, being the biggest problem. Because even though if you keep the individuals in, like this young lady who looks great and normal and is on her school cross country team, the appetite is all consuming. This girl has gotten suspended from school multiple times over the past 2 years. She's in high school. And she will sneak into the teacher's lounge during class transitions and clean out the teacher's refrigerator and eat all the stuff that's in there within the thousands of calories in just a few minutes, and we'll just basically shove the food in her mouth as fast as possible. Teachers don't really like this, so she often gets suspended if she is caught doing this behavior. And that's the thing is that these individuals are so driven for food that they will seek and steal food, they'll hide and hoard food. Again, as I mentioned, they'll sneak out of the home to try to get food. We have so many parents call us and say the police brought the child back home in the middle of the night. They were walking barefooted in their pajamas down a major highway to try to get to the McDonald's or the Jiffy Mart down the street to get to food. One of the more common causes of death is actually accidents because they won't do this behavior and get hit by a car, unfortunately, because often this behavior is at night. And so it's really just it's sad. But they are really amazing at how ingenious they are at trying to get to food. They like raw food, food from the garbage, non food items. 1 of my patients a couple of weeks ago watched on YouTube had a fashion lock pick out of a dowel rod and went into his neighbor's garage where they had a deep freeze and picked the lock on their deep freeze and ate 10 frozen pizzas before he was caught by the neighbor whose garage it was. And he was really pretty darn lucky because it was in the South, and everyone tends to have guns in the South. So I told him he was lucky he wasn't killed for being in someone else's home in the middle of the night eating 10 frozen pizzas. But again, it just speaks to the level of ingenuity and drive that these individuals have. Next slide, please. Right now, the only available FDA approved treatment for Prader Willi is growth hormone therapy, as I mentioned. This is FDA approved for growth failure in the syndrome, but most endocrinologists in today's world started in infancy at diagnosis. And the reason for this is that it has been shown to help with cognition as well as acquisition of motor and speech skills. There are several other medications that we routinely use in the syndrome for symptomatic improvements, things like sex, steroids and thyroid hormone replacement for the hypothalamic pituitary dysfunction and things like SSRI medications or stimulant medications for the rigid behavior, for the anxiety, for the excessive daytime sleepiness. Again, these relieve symptoms, but there is nothing that treats the hyperphagia, unfortunately. Next slide. So, right now, the way that hyperphagia is treated is by the house being a prison. As I mentioned, everything is locked. And the family of course are the wardens of that prison. So, you know, often the family will tell me that the other kids have to carry the key on a chain around their neck so that they can get into the cabinets when they want food or there's fingerprint locks everywhere or there's motion activated cameras. I mean, I can't even think that you could imagine the stress that this would put on a family to have to live like this. Next slide. And so, as I mentioned, this is an incredibly complex, difficult disease, and I'm sure you can only begin to imagine the impact that the COVID pandemic has had on individuals with this syndrome. As of the beginning of March, all of a sudden, these individuals who are extremely routine driven, who live on routines and black and white, no change, we're told you can't go back to school, you can't do your physical activity, you can't hang with your friends, you have to be at home locked in your house and you're going to do school virtually. And that transition was amazingly hard for these patients and their families. But you can imagine that that change in routine with no warning was absolutely cataclysmic for these families. And so next, Doctor. Strong is going to discuss the survey that the Foundation For Prader Willi Research did to try to capture the magnitude of the disruption on these families. Doctor. Schon? Thank you, Doctor. Miller. That was a great summary of PWS. And I'm really pleased to be here today and talk about the impact of the COVID pandemic on the individuals with PWS and their families. And this is a survey that we did over the last few months. Next slide, please. So, as Doctor. Miller has very nicely described, individuals with PWS face a lot of challenges as do their families. And because of this, families have typically built up a network of support to navigate all of these difficulties. So this may include a 1 on 1 aid in school, for example, to make sure the child does not go into the teacher's lounge and clean out the refrigerator. Multiple therapies, so our kids typically get speech therapy, occupational therapy, physical therapy, oftentimes behavioral therapy or social worker counseling, for example. In addition, families oftentimes are engaged in structured social activities and structured exercise, maybe Special Olympics, something like that. And some families also receive respite care, as you can imagine. And as Doctor. Miller has described, you know, there's a tremendous burden on the primary caregiver. And so, adjusting and allowing respite care is really important. We also talked about the fact that individuals with PWS thrive on change. And they have a real difficulty coping with transitions or unexpected changes or uncertainty. And as Doctor. Miller mentioned, we know this because of the behaviors. We see these behaviors really go up when there is an unexpected change. But we've also there have also been some very nice brain imaging studies using fMRI showing that they the portion of the brain that activates during task switching or moving from one thing to another does not activate in PWS. So, there's a biological deficit in their ability to navigate change and uncertainty. So next slide. So we understood this. We understood that families might have a very has hit everybody hard, it has more severely impacted the developmentally disabled population because of the disruptions to education, the social activities, as well as access to medical and the supportive care. So to try to get an understanding of how this is affecting families with Prader Willi Syndrome, we use the global PWS registry. So we have an active registry in which we are tracking natural history of PWS and we were able to develop a survey and put it into that registry and gather information from families with PWS. And in the survey, we asked about the stress on the caregiver. We asked about the challenges for the person with PWS, how they were coping, how their behavior had changed. We asked about access to medical care and prescriptions as well as to the supportive therapies and also asked about the transition in schooling since the majority of families with school age children move to remote learning. For the data I'm going to present today, we were looking at responses that came in between May when we opened the survey and August, the end of August. So, really trying to look back at that transition period in the sort of the March to June time. We asked families to answer the questions thinking about the time that was most impactful for them. And for this analysis, we pulled the data from individuals who had kids with PWS, kids and adults with PWS 4 and up and were living in the U. S. And the U. K. And that gave us about 300 or gave us 3 22 family responses. Next slide. So, the first thing we asked about was the caregiver, how the caregiver was doing. And not surprisingly, caregiver stress was considerably increased. So 85% of caregivers reported having a little or a lot more stress in their life. Their concerns included their primary concern was that their loved one with PWS would get sick with COVID and this is really a concern. Our kids with PWS oftentimes have a lot of the comorbidities that puts them at higher risk for having severe COVID. Parents were worried about if their child got COVID and had to be hospitalized that they wouldn't be able to be there with them. So, a lot of worries about that. There was also a lot of concern that the caregiver themselves again, the caregiver typically here is mom, that the parent or caregiver themselves would get sick and would not be able to take care of the individual with PWS. And for our parents of school age kids, there was a concern that, you know, that their education would fall behind their peers during this time. We also saw that caregivers, if their change in sleep, if they had change in sleep, it was usually getting less sleep with the pandemic. Next slide. We asked again about access to medical care and access to therapies. And what we found was the vast majority of families felt like they were getting the medical care that they needed. So more than 90% said that, you know, especially through telemedicine, they were getting access contrast, the access to the therapies was really decreased. So, 60% to 80% of the time, they were either completely eliminated or severely reduced. So the physical therapy, the occupational therapy, speech therapy, behavioral therapy, therapy, access to psychological counseling were all really severely impacted. We asked the caregivers overall had of the individual with PWS become easier or more difficult to manage. And whereas about 45% of families said that it was about the same, a good portion, more than 40% said that it was harder to manage the behavior of the individual with PWS. Next slide. And we looked at that a little in a little bit more detail here, some of the behaviors that we commonly see in PWS, sadness, self injurious behavior, repetitive and OCD kind of behaviors that Doctor. Miller had talked about. And in each case, there was, you know, probably about half of the population had about the same level of behavior. But where the behavior changed, it generally changed to be much more difficult. So, particularly in the area of food seeking, which as Doctor. Miller mentioned is very common in PWS, those behaviors were considerably up and the stress and anxiety were considerably up. And this is really not a big surprise given what we know about PWS. So these kids were having to transition. They had a schedule. The schedule was completely disrupted. And now the families were having to step in. And what we heard from families were the routine has changed. They don't have as many activities to keep them busy. Now they can really think and perseverate about that food and really increase their food seeking. And families were having to step in and really try to think of, as we all were, but exponentially so for those with PWS, what can we do to engage the individual with PWS, keep them busy and keep them focused on positive things rather than on some of these negative behaviors. So overall, a lot more difficulty with the behaviors which are already very difficult in PWS. Next slide. We also asked about sleep, weight and physical activity and social interaction. By and large, the amount of sleep stayed about the same, maybe even a little bit more. But what we heard from families was the lack of structure caused disruption in the sleep schedule. So, our kids tend to have disruptions in their circadian rhythms anyway. And then as we move to this loss of structure, that became a problem for a good number of families. Weight, in some cases decreased because, kids didn't have as much access to outside areas, but in more cases it increased, when they were kept at home. And that may be in part because of the decrease in access to physical activity that most of the families experienced. And finally, I think as we can all appreciate the social activities really decreased for our kids with PWS and some of them are able to adapt to Zoom meetings and some of them just are not. And so it was very isolating for a lot of individuals. And again, in some cases was feeding this bad behavior, focus on food, more temper outbursts, that was common. Next slide. So in summary, individuals with PWS and their parents and caregivers experienced significant disruptions during the COVID pandemic. The caregivers experienced increased stress as they took on all these additional responsibilities that they typically have support for the education, for the therapies, for the exercise. So they suddenly had to become speech therapists and OT and also be the exercise warden and the activity coordinator for the individual with PWS. Those decreased social opportunities that change and that transition, that's what really is difficult for our kids and really increase the stress and manifested in many cases as increased behavioral challenge. And parents really cited that the inability to tell their child when are we going to go back to school. So kids with PWS ask repetitive questions anyway and we had parents, we had free text boxes saying, you know, she asked many times a day, when am I going to school? When am I going to school? When am I going to school? And not being able to give them that answers was really stressful. So we're all looking forward to hopefully, you know, moving forward and moving through this pandemic and getting back to something closer to normal. And I think I'll pass it over to Anish. Thank you, Doctor. Strong. I'm going to go into what we think the impact has been on the DESTINY PWS data. As you heard from Doctor. Strongstock, clearly, a number of things happened during this pandemic, which could impact the data, particularly the subjective endpoints in this study. Next slide. So, we undertook a comprehensive analysis based on a number of sources of information. 1 was a published statistical guidance from the FDA that came out in the middle of June after our top line data was analyzed. Other industry publications that were relevant published literature which talks about the impact of COVID, particularly on childhood psychiatric conditions. And obviously, the data from the FPWR that Doctor. Strong just talked about. Our expectation was that there would be changes seen in the more subjective endpoints, whereas the more objective endpoints that were positive in any event for the most part in the top line analysis would not change much. Next slide. So, just to remind you of the cadence of the study, the last patient was randomized in late January of 2020, last patient last visit was April. And the top line data was received in early June of 2020. COVID was declared a public health emergency in the U. S. As early as January 31, 2020. And a national emergency was declared as of March 1, 2020. We considered March 1 as the choice for the cutoff date for various reasons. It appears to be the best day to look at what's a reasonable pre COVID cutoff, which means that COVID perhaps did not substantially impact the data at that point. And this has been used by other sponsors anecdotally, including some in the PWS space. So, as of March 1, 86 subjects or 69% had completed 601. Next slide. To remind you a little bit about the endpoints in C-six zero one or DESTINY PWS as our Phase 3 study was called, The primary endpoint was mean change from baseline and hyperphagia. Hyperphagia was measured by a tool called the HQCT, the hyperphagia questionnaire for clinical trials. It's a 9 question questionnaire. The scores are 0 to 4 for each question. So, worse hyperphagia is 36. It is obviously a subjective endpoint because the caregiver is the person who fills this out. The other subjective endpoint was the caregiver global impression of change. It was one of the 3 key secondary endpoints. The other 2 were more objective. So, the CGI or the clinical global impression of improvement, which is done by the investigator and a change in body fat, which is done by DXA, which is an x-ray technique. So, in other words, 2 of these four endpoints were subjective and 2 were objective. The subjective ones did not have p values of less than 0.05, while the objective ones did in the primary analysis. Next slide. What we see with the analysis of data through MARCH-one is that the primary as well as all three key secondary endpoints are statistically significant. If you look at the columns on the left, the all data columns are the top line analysis. You see the p value for the primary endpoint is 0.198 and that of the caregiver GIC is 0.41. Those were not less than 0.05 obviously, while the objective endpoints were. I'll go into some more detail into these analyses. Next slide. The primary endpoint is the change from baseline in HQCT. What we see in the active group is 6.6 4 -6.64 and placebo -0.31, a least square mean difference of -3.13 and a p value of 0.0 37. This analysis is a linear MMRM analysis that takes into account all data until March 1. So, in other words, all patients enrolled until the end of study, but data as of March 1. This is the same analysis as was performed for the primary endpoint in the top line. Next slide. To look further at this analysis, it's not that March 1 was picked because it was significant that day. What this forest plot shows you is how the P value changed over time. This trial was significant as of January 15 and remains so until the middle of March. So what you're seeing here is the 95% confidence intervals around the change from baseline and hyperphagia for DCCR versus placebo. When the 95% confidence interval bars are within the vertical line that you see, the p value is less than 0.05. The p value trended towards significance as early as December 1, as you can see, significant on the 15th January in 2 week increments until March. So these are P values that start in the October on 1st October 2019 where there are very few patients on study. As more patients come in, the 95% confidence intervals tighten and you see significance coming in, in January and staying through the middle of March. Next slide. We've also looked at the waterfall plot of these patients, which is all patient data changed from baseline in hyperphagia. DCCR is in green. Placebo is in blue. The lower the bar, the bigger the response. So, the largest responders are towards the right of the slide. And as you can see, virtually all of those are green, which means if you're in DCCR, you're extremely likely to have a higher response compared to placebo. Next slide. One of the questions that's often asked is what is a clinically meaningful change? And the way the FDA wants you to calculate clinically meaningful change is based on several anchors that are measured within the same trial. So, we use an external group to measure a clinically meaningful change that takes into account anchors such as the clinical global impression of improvement, the caregiver global impression of improvement, the overall, the food related behaviors, etcetera. And the optimum threshold for response is determined to be at least 7. And when you use that change of 7, 53% of DCCR patients had a response whereas 28% of placebo patients had a response, whereas 28% of placebo patients had. And that difference has a p value of 0.028 with an odds ratio of 2.94, statistically very significant. Next slide. In terms of the secondary endpoints, this is the data for the clinical global impression improvement or CGI eye. What you're seeing here is that 40% of patients improved on DCCR compared with 6.7% on placebo, a p value of 0.015. This is using all data, no data imputations until March 1. Next slide. The caregiver global impression of change, which was not positive in the top line analysis, you see 40.8% patients on DCCR are better versus 20% on placebo, so twice on a percentage basis, a p value of 0.031. Once again, all data not using any data mutations. Next slide. The fat mass, which was positive in the top line analysis, remains so and statistically more so. You see a significant decrease in body fat with the active, which is green and blue, which is placebo, p value of 0.004. Next slide. We looked at several behavioral endpoints. And in general, as you would expect, based on the disruptions described by Doctor. Strong, we expected to see improvements in these behavioral endpoints and these data are illustrative of what we are seeing. The PWS profile questionnaire tracks PWS behaviors in 6 different domains. So, aggressive behaviors, anxiety, rigidity, compulsivity, depression and disordered thinking. You see statistically significant changes in 5 of these 6 domains. The other one, depression, is trending towards significance. These behaviors, as Doctor. Miller mentioned, are really important to these families. And it's interesting to see the changes across the board in all of these behavioral domains. We've also mentioned here the DBC2, the developmental behavioral checklist. This is interesting because this looks at behaviors in a way that's different from PWSP. The PWSP is more of an inward looking analysis of the subjects' behaviors. The DVC-two has 6 subscales and 2 of these subscales, the communication disturbance and social relating, they relate to how these patients interact with others. And the total score on DBC2 was statistically very significant with a P value of 0.009. And while all the others were trending, the 2 that were most significant were communication disturbance and social relating. Next slide. We've analyzed the data in many different ways. There are no significant differences in the demographics compared to topline ITT population. In general, DCCR shows statistically significant improvements in several subjective endpoints, which were not positive in the top line analysis. Objective endpoints were mostly significant in the top line analysis and generally remain so. Safety profile was similar to what was observed in the ITT population in the top line analysis. Next slide. So in conclusion, there's a clear impact of the COVID pandemic based on Doctor. Strong's data on caregivers and subjects who were involved with PWS as well. Primary, subjective key secondary and several efficacy variables are significant with this pre MARCH-one data. We've seen no differences in the safety of DCCR compared to the profile seen in the top line analysis. So, I'm going to now pass it back to Doctor. Miller to talk about the impact of DCCR on her 601, 602 patients. Doctor. Miller? Thank you so much. Next slide, please. So this that I'm going to talk about is actually just my personal observations of my patients that were in the 601, 602 studies. I was the largest enrolling site for this study. But additionally, I have a huge clinical practice. I follow over 5.50 individuals with Prader Willi from around the world. So I did have the benefit of many patients that I would see in clinic who were involved in this trial at other sites and even in the U. K. So I got to hear a lot of stories about the DCCR trial from a variety of patients, and I got to see them myself and my patients that were enrolled in study. So these observations obviously do not apply to every patient, and they're just some observations that I personally noted from my patients when talking to them and observing them. Next slide, please. So in prior willy, as I mentioned, the loss of the 16, which leads to an excess of 2 neurotransmitters that are potent hunger hormones, excess of 2 neurotransmitters that are potent hunger hormones, neuropeptide Y and a gooey related protein. And those hormones will, of course, directly increase hunger, and the exacerbation of leptin resistance and insulin resistance leads to even higher levels of these hormones. And so all these physiologic changes that then cause physical changes and behavioral changes are happening and getting worse through time. And of course, unmanaged hyperphagia, which then leads to increased weight, which leads to increased leptin and insulin resistance, will then, of course, further fuel the cycle. So it becomes almost an unbreakable, rather horrendous cycle that typically occurs in Prader Willi syndrome. Next slide, please. So when I mentioned earlier about how we see children with Prader Willi progress through these various nutritional phases, it was fascinating to watch the results of the DCCR trial in that the changes that occurred with DCCR actually occurred in exactly the same way that we saw them occur with the progression through nutritional phases. So first thing we saw was improvements in those biochemical changes. So leptin decreased, adiponectin increased, and insulin decreased quite significantly. And then over time, those biochemical changes led to the physical improvements that you just heard about from Doctor. Bhatnagar that there was improvements in fat mass and increase in lean muscle mass. And then subsequently, those physical improvements seem to lead to behavioral changes. So we saw the improvements in hyperphagia and the improvements in all those behavioral domains that you just heard about aggressive behaviors, anxiety, rigidity, compulsive behaviors. And so it was really very interesting to watch how this transition took place and the fact that it did take actually quite a while for it to take place because it sort of followed this pattern predictably in every patient that we saw. Next slide. So, what does it mean? What Doctor. Boddingar talked about was the clinically significant change in the hyperphasia questionnaire. And for me as a clinician, what does that actually mean? And for parents, what does it mean? Well, it's actually what it means is that the individual is not thinking about food all the time. So typically, as I mentioned before, these individuals are exceedingly driven to get to food. They're constantly thinking about food, smelling food, hearing someone opening a bag of food, whatever, it focuses them on food and they cannot be distracted from it. And on this trial, what we saw is that no longer was a top priority. They could easily be distracted about food, meal times were relaxed, and people would skip snacks, and kids would leave food on their plate when they were done eating, which the parents would go, well, that never happened before. You know, I mean, it was quite remarkable. Many of our families unlocked the refrigerator, they turned off their cameras. I can't even tell you the number of families that I heard say that they forgot their child had Prader Willi syndrome, which is just was mind blowing to me. I can't, I could never imagine such a thing, but you can imagine when you're no longer living in that prison that I, that it could happen. They were able to take their kids with probably to the grocery store. They could help them grocery shop to restaurants and to family gatherings. And what was most remarkable to me was even the siblings wanted to take the kids out because it used to be again that there's such a level of resentment and stress from the siblings of these individuals. And with the kids on trial, I mean, we would hear story after story of, oh, well, our daughter took our other daughter to Olive Garden for dinner because and it was just a perfectly pleasant experience. I mean, again, things you would just never hear of. 1 of our adult patients, her mom was able to give her the checkbook and send her on a bus to the grocery store to get groceries, and she would never buy anything she wasn't supposed to, and would come home with the groceries intact. It was really just quite remarkable, and the behaviors, of course, improved around food. There was less temper tantrums, less severe temper tantrums, less aggressive behaviors. Next slide, please. Then as Doctor. Bodnar mentioned from the questionnaires that were done, you did see those manifest clinically as well. Tremendously improved family dynamics, social interactions. The parents were just stunned by the fact that now the siblings actually liked the probably they would be able to sit around and have conversations with them because previously the kid with probably would be so stuck on whatever they wanted to talk about or whatever they wanted to focus on that it wasn't a conversation, it was a monologue from the child with prodderellae. But now they were able they report that they're able to sit down and have actual discussions. And even I could see it in clinic and in the research center when I would have patients in, we would talk about their friends or their schoolwork or their tennis shoes. I mean, not just whatever it was that they wanted to talk about, which is usually what it was at the very beginning. There was less anxiety and what that translated into was less repetitive questioning. And I had a family in today and I asked the mom, tell me when what was the most significant impact that DCCR had on y'all's lives? And her answer was, I don't want to kill her on a regular basis. And that made me laugh, but it was because she said, she used to ask me a thousand times a day about things, and it just went on and on and on, and I couldn't stop it. And now she doesn't do that anymore. Now it's one and done. She asked me a question. I answer it. We're done. We move on. And she said, you have no idea how life changing that is. There's decreased compulsive behaviors and skin picking as well, which is, again, remarkable. These kids skin picking is a really big issue in Crodderellia, and it's associated with anxiety. And we would have kids in the trial that had had lesions that were open for months months months. And while it didn't completely stop on trial, it actually did decrease quite significantly. Next slide. The improvements in body composition resulted in increased strength, stamina, exercise capacity. So these kids were able to do things that they normally wouldn't do. 1 of the moms, I'll never forget, called me up and she said, my kid is outside rollerblading. Did you ever think a kid with Prada Willi could rollerblade? And I was like, honestly, no. And she said, me neither. So it was pretty cool. They're riding 2 wheel bikes, they're running. One of the kids on trial, actually, we have every year a fundraiser event in January. And this girl who's 15 ran a faster 5 ks than I did. She ran a 27 minute And it was just it's truly incredible. And what it means is that they have increased voluntary exercise. When exercise is easier, they do it more. And we certainly saw this in a lot of patients, and then as well as just an overall sense of well-being because that's what exercise does. Next slide. And so this is the results. This is one of the more dramatic results, obviously, from the trial. Not everybody had this degree of response, but we did have several people who did. And this is the results of someone that baseline weighed about 121 kilos. And you can see that after 12 months on open label for DCCR this year, about a month ago, he weighed 94 kilos. We had an almost 30 kilogram weight loss. And you can see that what happened was that was almost actually, it was exclusively fat mass. So he lost half of his body fat with this weight loss, and he had improvements in his lean muscle mass. So I've been working in product really for about 25 years, and I can honestly say that this is contradictory to the natural history of the syndrome, in that most of the time when individuals with Prader Willi lose weight, they lose both fat and muscle. And when they gain weight, they gain both fat and muscle. And in this case, as you can see, what happened was this kid not only lost a significant amount of weight, but he lost exclusively fat weight. And amount of weight, but he lost exclusively fat weight and actually had an improvement in his lean muscle mass, so it was just it was really amazing to see. Next slide. And this, of course, as I mentioned, is manifested by these changes in the biochemical markers, and so there were significant reductions in insulin levels from baseline as well as in leptin levels. And adiponectin increased because they had a decline in fat mass. And what was most interesting to me is typically with Prader Willi Syndrome, when leptin and insulin decrease with weight loss, what happens is ghrelin, which is your hunger hormone increases. And I think this happens in everyone in the population that when we start to lose weight, our body's like, oh, we're not supposed to be losing weight. Our leptin and insulin are going down. We don't have adequate fat stores. And so ghrelin goes up to try to make you eat more. And in this case, with DCZR, what we saw was that ghrelin actually went down. So again, very contradictory to the natural history of the syndrome. Next slide, please. And so one of the things that Doctor. Bhutnikar mentioned is the clinical global impression of improvement that we do as investigators. And so this allows us as the PIs to think about the whole patient, not just the hyperphagia questionnaire or the behavioral questionnaire or whatever. We actually get to assess everything, to talk with the families and assess what's happening in these individuals. And as I mentioned before, you can see on the left, the typical product related patient where there's these biochemical changes and physical changes and behavioral changes that all sort of cycle in a very negative way. And when we introduced DCCR in a lot of our patients, what we saw was exactly the opposite. Again, there was improvements in these biochemical changes, improvements in physical body composition and improvements in behaviors. And it was just it was really, truly stunning to watch. Next slide, please. So, the adverse event profile for DCCR is known and is consistent with that of diazoxide, and DCCR has been trialed before, and it was no different in this trial, the safety profile than it was in previous trials. The most common adverse events that we saw during the trial were hypertrichosis or increased body hair growth. There was increases in blood glucose levels because of the mechanism of action of the drug, and there was some edema, particularly in adult patients with potterly. But given the significant unmet need in this syndrome, I truly believe that DCCR has a very desirable risk benefit profile. So the data to date suggests that there are clinically and statistically significant benefits to individuals with Prader Willi Syndrome, and they appear to span both behavioral as well as metabolic endpoints. And I just I want to put in a story here. I like to tell stories because to me it really illustrates the effects that we saw. And one of my favorite stories from this trial is of a young lady who was 10 when she enrolled. And the very first day on trial when we were screening her, I took food away from her because she was eating something that she wasn't supposed to. And she had this massive meltdown in the middle of our research unit. She threw the crash cart to the floor. She threw my study coordinators, a bag of charts to the floor. She was hitting people. She was turning over beds. I mean, it was insane. And this lasted for about an hour and a half. I actually had to kick her parents out of the room while I dealt with it because they were not dealing with it appropriately. And it lasted for about an hour and a half. And then she came in last Tuesday and she's been on 602 for over a year now. And she was sitting there and they were running late because dad had forgotten to set the alarm and whatever. And so mom pulls out breakfast and the kid looks at her and she says, mom, where's my orange? She promised me that I could have an orange for breakfast. And our mom said, oh, my god. I'm so sorry. I forgot. We were running late. And the kid goes, okay, and proceeds to eat her eggs, and the mom looked at me and my coordinator with just tears running down her face, and she's like, this. This is what this has done for us. She's like, you don't understand the profound impact this has had on the mental health of our family, to see how much this child's reaction has changed to things like that. She said, you know what she used to be like, you've known her since she was 2 months old, and look at this. And then they put down half of her eggs and said, I'm ready to go to the DEXA scanner now, Doctor. Miller, and left half of her breakfast sitting there on the table. So I mean really, really stunning results for these families. And again, these are anecdotal experiences. These are not every person in the trial, obviously. These are just my observations, but truly remarkable to see. And so, potential potentially change the natural history of this syndrome. Thank you, Doctor. Miller. My name is Jim McInnis, and I'm the Chief Financial Officer of Salino. We thought we'd end this presentation with just a couple of slides and a few comments on the commercial opportunity for DCCR as a treatment for PWS. We think there's a number of positive attributes that make this a very attractive market. Next slide. So PWS is a rare disease, but there is a fairly substantial patient population. If we look within the U. S, for example, overall, U. S. Diagnosed PWS prevalence is about 2.7 per 100,000, which leads to about 8,000 to 800 estimated patients diagnosed with PWS set in the U. S. If we look in the table on the right hand side, you'll see the prevalence per 100,000 by age. And what you'll notice is once we get beyond 26, the prevalence rate drops significantly. And this is consistent with the elevated mortality rates and a ME life expectancy of approximately 30 years. So all told, what this concludes to is an estimated current U. S. Prevalence of approximately 10000 to 20000 individuals and then obviously beyond the U. S. As well. Next slide, please. So the primary treatment for patients suffering from PWS is predominantly pediatric endocrinologists. Although there's approximately 1,000 pediatric endocrinologists in the U. S, less than 150 specialized in treating multiple PWS patients. For example, you find the 70 listed on the PWSA USA website. There are for the adult patients, adult endocrinologists and other practitioners. And there's a small number, but growing centers with multi disciplinary clinics where treatment is available. There are active patient advocacy groups, as you heard earlier, Doctor. Strong from the Foundation from Prader Willi Research as well as the PWSA USA. PWSA USA has state level chapters in most states. And we think these dynamics afford the company the opportunity to be able to educate, message and ultimately sell into the patient population through a relatively small commercial footprint. Next slide, please. Other positive attributes that we see in this market is obviously no alternative approved treatment. The drug itself is straightforward to take, straightforward to distribute. It's a once daily tablet delivered in bottles. The patient environment, as you've heard, is highly structured with defined routines. This would suggest higher than average compliance and adherence for patients once they are on drug. And the distribution follows the standard 3PL specialty pharma and hub to get to the end patient. And we expect DCCR to attract orphan pricing. Next slide, please. So beyond PWS, we think there are also other indications that provide opportunities for DCCR. We group these into 2 groups. You can see the syndromic obesity indications. These are PWS like. And then also there is, for example, chronic hyperinsulinism and glycogen storage disease type 1, where historically, dizoxides has shown some levels of efficacy. So we think there are other rare indications beyond just PWS. Next slide, please. So really, just to emphasize the key takeaways. PWS is a rare disease, 10000 to 20000 people in the U. S. DCCR is treating the highest unmet need for which there is no approved treatment. So a very simple product in a daily tablet formulation with attractive with orphan pricing. And the commercial footprint that we think necessary to reach this patient population is, as I said, relatively small. And then beyond the PWS, we think there is substantial potential upside in other rare disease indications. And so with that brief slide presentation, I'll turn it back over to Sarah for the Q and A session. Thank you, Jim. At this time, we'll be conducting our Q and A session. As a reminder to the audience, if you'd like to submit a question, please go ahead and use the Q and A function at the bottom of your Zoom app. So, please hold while we poll for questions. So, the first question comes from Leland Gershell at Oppenheimer. Leland, please go ahead and unmute your line. Great. Should be unmuted. Thank you. Thank you for presenting this very compelling dataset. And thank you, Doctor. Miller, for your additional all your commentary. A couple of questions. The presentation and analysis around the kind of timing dependence of data subject to the COVID environment and situation, this is the first time that I've seen trial data analyzed according to this paradigm. Wanted to ask if there are any other examples that you might be aware of or any who are on the call in which other trials perhaps by others that you just may be aware of whether other indications, what other settings, what have you have been analyzed accordingly and have provided similar support with regard to the kind of change in subjective endpoint, particularly analyses from pre March timing to after March? And then I've got a follow-up 2. Thank you. Thanks, Leland. So, I think it is too early to see lots of analyses like The pandemic is still ongoing. And I think some indications lend themselves to a lot more effect than others. There's been a lot of publications now and some in particular, one we referred to in my presentation, which talks specifically about the effects of the pandemic and the transitions and the disruptions on the pandemic on childhood psychiatric conditions. So, there's a growing body of literature that talks about how to So, I don't think there is much that's been done so far will be done soon. So, I think we're trying to do this in a comprehensive way using all the parameters that have been described in the literature. Okay. And then it takes me to my next question, which is to what extent and maybe you'd said and I'd missed this and I apologize if so, have you discussed this analysis particularly in particular with the FDA and the division with regard to how they may interpret the data the way you are? So, these analyses have been submitted to the FDA. They were not part of the discussion that was had earlier. So, we'll have to wait and see what they say. Okay. And then one last question just for Doctor. Miller. So, as I said, to my eyes, at least this looks like a very compelling data set for DCCR and PWS. I'm wondering if there are any unanswered questions that these data leave on the table for you with regard to DCCR, with respect to more time required on therapy to maybe understand the waning of effect, maybe there's not sure if you have any concerns there, maybe that's just an unanswerable question. But we'd just like to hear if there's anything that we haven't answered about DCCR's potential in PWS from either an efficacy or safety perspective from the data sets we've seen so far. So you may have talked to me before. I know that I'm a pessimist in some ways with regard to long acting effects of drugs in this syndrome. And I have to say, we have patients that have been on trial for up to 2.5 years now. And at the Seattle site, there's someone who's close to 3 years at this point. And we see no waning of efficacy at all during that time, which is stunning to me. I kind of still keep waiting for the other shoe to drop. But honestly, I mean, I have 29 patients at my site and we have really not seen we've had no dropouts. We've had nobody have waning of efficacy other than as you would expect, as these are growing children, they're growing, they're gaining weight, they're going through puberty. We do have to change dosing as you would expect for any hormonal manipulation as these kids grow and change. But other than that, no, I mean, it's really been really stunning to me to see this. And I really I learn from the I really, at this point, don't really have any unanswered questions. I do think we learned through 601 that it does take a while to see those behavioral changes longer than we would have hoped. I think parents wanted an immediate response, which did not happen. I mean, it took a while to go through those biochemical changes and physical changes and then the behavioral changes. But nonetheless, at this point, everyone And And I'm really not left with any remaining questions at all. So the next question comes from Etzer DeRue at Guggenheim. Please unmute your line. [SPEAKER UNIDENTIFIED COMPANY REPRESENTATIVE:] Great. Thank you for today's presentation. A lot of great insights here on PWS. And so I guess question for Doctor. Miller. You've noted biochemical, physical and behavioral changes with DCCR. So I guess how do you prioritize these changes where you see clinically meaningful benefits, right, with the drug relative to sort of the natural history of patients? And I guess how durable do you think these benefits should be to see either significant adoption by patients or even sort of meaningful differences in the eye of regulators? I'm not sure I definitively understand the question, but I'll do my best. And if I answer incorrectly, you can correct me and restate. But honestly, the physical characteristics really remarkably, again, I argued many times for many other drug companies that physical changes were not a high priority in this syndrome, that it was really the hyperphagia that was the life limiting step here. But these physical changes have been really remarkable in terms of quality of life. And so and the great and remarkable. But honestly, the physical and behavioral changes are what great and remarkable. But honestly, the physical and behavioral changes are what matters, right? And so I've been stunned by how many parents just hold those DEXA scans in their hands at the, you know, when we get them on visit 15 of 602 and, you know, I'm showing them, you know, the results. And they're just crying to see the changes in their kids' body composition and to tell me story after story of what their kids can now do physically. And I think that's really meaningful. And the changes in behavior, of course, are hugely meaningful for these families. I mean, you've heard from Doctor. Strong about how bad COVID changed the things that are the natural history of this syndrome, and you heard from me how bad the natural history of this syndrome actually is for families to live through, and it really has been remarkable. I've had at least 5 families of my patients between my site and just clinical patients tell me they were on the verge of divorce before this trial. And one of the families actually who spoke at the FDA for this trial, they were actually they had moved out from each other and prior to this trial and had come back together and are now living together again and said their marriage is significantly better to have the decreased stress from everything that was going on with this kid, because I mean, I don't even know if you can imagine living with your kitchen completely locked down with padlocks and cameras and you can't let your kid out of the house and you have to watch them 20 fourseven. I mean, it's an amazing amount of stress. And so even a little change, I think, would be beneficial. And I've always said that anything that could take the edge off, I think, would be beneficial. This, again, has had, at least in my experience, effects that were completely unexpected for me in terms of reducing some of these core symptoms of Prader Willi that I would have never expected. The first patient that came and told me her OCD was gone, that the mom said the kid's OCD was gone. And I said, nuh-uh, that's not how the drug works. And she was like, Her OCD was about that she had to pick out her outfit, and it took her 2 hours every night before school to pick out her outfit. And now she just goes in in the morning, gets an outfit, and puts it on, and goes to school. Mean, this is not the natural history of the syndrome. And Doctor. Strong can tell you that with great certainty that this is not the natural history of the syndrome. These things don't just get better. They get worse or stay the same. And so to me, that was all those findings were really huge. Did that answer your question? No, yes, absolutely. Thank you for that. And I guess, Anish, as a follow-up, I guess, have regulators expressed the endpoints they view as most meaningful, I guess, with what Doctor. Miller has just said? So, in terms of the regulators' opinion on the endpoints, that was, I would say, best reflected in the discussions on the Phase 3 design. So, I don't think anyone argues against hyperphagia being the most important and therefore the primary endpoint. I think the caregiver and the clinical global impressions of change and improvement are important. Body fat, as Doctor. Miller is pointing out, is important as well. I think what we believe is that all these subjective changes are really important to these population. But we believe it's also important to see the objective changes that we are seeing because they sort of confirm that what you are seeing on the subjective side is being manifest in a way that's easily measurable. So, it's not to say that these discussions have had in this way with the regulators, but I think any reasonable person would think of the endpoints in that way. Great. Thank you and thank you for the update today. Thanks, Tata. The next question comes from Yale Jen at Laidlaw. Yale, go ahead and unmute your line, please. First of all, thanks for offering this very insightful presentation and especially this COVID nineteen impact is very, very interesting. Just 2 or 3 short questions. The first one is that you have a cut off date as of March. Is there a possibility you could also maybe, let's say, having a cut off day of beginning of April to see that continued to have that impact. So maybe potentially strengthen your arguments in terms of the COVID pandemic impact is very consistent so strengthen your arguments for that. Thanks, Yale. So, I had shown a forest plot of the P values of the HQCT analyses over time. And what we are seeing is that the trial was trending towards significance late in 2019 and became significant in the middle of January and continued to be so until March when it starts to lose significance. So this to us is consistent with the transitions and the disruptions that are seen with PWS. And pandemic, the trial, the subjective endpoints would worsen as you go deeper into the pandemic, while earlier and before the pandemic, they should be positive. And what we've seen in all the subjective endpoints and indeed in all the objective endpoints is that trend. Okay, great. And two quick questions. First one is that earlier you guys mentioned that you're going to do a natural history study based on the existing data. Is that still will be a task to be accomplished at this moment? Yes. So, what we had said was that we one of the things we are trying to do is to compare our data, particularly the long term data from 602 with, A, the FPWR path for PWS study where HQCT is captured in 6 months time intervals over time. And with the natural history study, that was the NIH sponsored study, which was led by the University of Florida and Doctor. Biller's group to look at more objective body parameters of PWS. So that is still in the cards. We are working on the analysis plans. We are thinking through how the March 1 analysis impacts that data. But, yes, we are still working on those. Okay, great. And maybe the last question here is that given probably you guys are a trailblazer in the way to analyze the COVID impact, particularly in these subjective endpoints. So on with this, without telling us too much of your actual sort of thoughts, any sort of general idea of how would you discuss with FDA having these potential adjustments of the data or different view of the data and maybe or potential approval, what could be the options you can contemplate? [SPEAKER DOCTOR. JOSEPH BELANOFF:] Joseph Belanoff:] I think a good way to think about this is that the March 1 analysis represents a data set that the trial was designed for. So, we designed the trial for a world where there was no COVID. And March 1 represents that time. So, our analysis, based on the published literature, the statistical guidance, etcetera, is really driven by that fact that the primary estimate of interest remains the same with the March 1 analysis. So, we hope that people would see on the regulatory side would see it the same way that this is the appropriate way to analyze the data as a primary analysis. So, I can't say much more than that, but I think that's probably the best way to answer the question. Okay, great. I really appreciate that. And certainly, this is a give us a much sort of fresh view of the data before you guys present this and really appreciate it. Thanks, Yale. Thank you, Yale. So this concludes the verbal portion of the question and answer session. I'll now turn the call over to Brian Ritchie of LifeSci Advisors for any questions that may have come in over the web. Thanks, Sarah. Let's start with one for Doctor. Strong. I think we have time for a few here. So, now that the pandemic has continued for nearly a year, should we expect PWS families to be getting more accustomed to their new routines? Yes, I think we're seeing some of that and that's why we decided to just look at the data up until August 31. So going into the new year for kids, there was, at least in some cases, some certainty that they were either going to stay at home or go back to school. Parents have I mean, in many cases, they've had job changes or whatever, and that sort of settled in as well. So, yes, I think to some extent, I do think that families would really welcome the change where they could be getting back to having that additional support. There's a as we've discussed, there's a big burden on the family and you really need a network of people to kind of help the person with PWS as well as the family's mental health. Great, thanks. Maybe now one for Doctor. Miller. Maybe Doctor. Miller, can you discuss your thoughts on the pros and cons of of action? Sure. And so the mechanism of action is the targeting of these potassium ATP channels at various tissues in the body. And so I have to say, having done the trial, at first, I had concerns that maybe this wouldn't be the same, the potassium ATP channel action in all these various tissues. But having done the trial, seeing the safety and side effect profile of the drug and having done many clinical trials over my career, I can say that this mechanism of action actually is seems to be safer and more effective than the other drugs that I have been involved with the trials, those like targeting the met ATP channel, the ghrelin inhibitors, goat inhibitors, oxytocin, that kind of stuff. It seems to be that this is having a more sustained effect than anything I've seen and also a safer effect. I mean, as we all know, there were some of those drugs that were fatal, dangerous. And so we certainly have seen no indication of any severe adverse events with this mechanism of action. Great. Thanks. Maybe, Anish, one for you here. Was the proportion of patients on growth hormone the same in the March 1 cohort as the top line cohort? They were. Both the top line cohort as well as the March 15 cohort had between 80% 85% of patients in active and placebo groups have on growth hormone. And as you know, the median age of subjects in the top line analysis was also about 13.5 years. So virtually all of these patients in the U. S, you would expect to have on growth hormone. So it's not surprising. Great. Maybe we're sort of running out of time here. Maybe one last question, Anish, that I'll ask you. Maybe just to summarize your thoughts on the overall impact of these sort of pre COVID data and how important you view them? I think these are important. And we have believed from the time of the top line analysis, even though the primary analysis was negative, we have believed that the totality of evidence made it clear that there was a drug effect. It was disappointing to see a primary that was not less than 0.05. These data bring it all together for us in the sense that, yes, it was very likely a COVID impact that drove the trial towards a negative primary. And it's good to see that all the objective as well as the subjective endpoints are lining up in the same direction. So yes, I think it's very important, not just for us, but I think even others who look at these data from the outside should feel that way. Great. Maybe with that, Anish, any closing comments? No. Thank you all for listening. This was a great session and thank you, Doctor. Miller and Doctor. Strong for your time and all the interesting insights. And thank you LifeSci for hosting this.