Morning, everyone. Welcome back from Labor Day weekend, and thanks for joining us to listen to this KOL panel with five pediatric endocrinologists to discuss pediatric growth hormone deficiency, or PGHD, in the context of the upcoming final data set from Lumos' phase two trial with LUM-201, which would be the first oral once daily pill for PGHD. I want to set the stage for our discussion with our KOLs with two slides. The first is going to show the mechanism of action for LUM-201. That graph in the yellow box is a representation of the PK profile for the natural growth hormone in normal individuals over 24 hours and shows what is called a pulsatile profile. Almost exactly 38 years ago, it was October of 1985, Genentech had the first FDA approval for recombinant human growth hormone called Protropin to treat kids with growth hormone deficiency, and it's been the standard of care ever since. It was actually the first biotech drug ever approved. There's now lots of different brands now, lots of different versions of recombinant human growth hormone, but they're all daily injectables that simply replace the natural hormone that's lacking in these kids. But what you don't get is that pulsatile type of release. It's just, constitutively high, and that's why I brought it up. The LUM-201 is Lumos' oral growth hormone secretagogue. It stimulates the release of endogenous growth hormone, and as a result, it can restore that more natural pulsatile release of growth hormone and can be subject to the natural feedback mechanisms for regulation. The big reason that Lumos is studying more moderate patients that are included in its trials is that if these patients were completely deficient in their ability to release growth hormone, there would be nothing for LUM-201 to stimulate, so it wouldn't work. The more moderate patients still have some level of growth hormone secretion, and therefore, LUM-201 just helps to increase that amount to more normal levels. So in terms of the data, remember, Lumos reported interim data from its phase 2 trial back in November on 40 patients. They expect the top line results on the full number of patients, around 82, in the fourth quarter. There's 20 patients in each of the four arms, 0.8, 1.6, 3.2, and recombinant growth hormone is the active control. They'll also release data from 22 patients from their phase 2 OraGrowtH210 trial at the same time. Importantly, remember, it's not statistically powered to prove non-inferiority to any one of the 201 arms compared to the active control. The primary endpoint is simply annualized height velocity, the very standard endpoint at 6 months. But they're also expecting to release data from a smaller number of patients treated for 12 months and for 18 months at the same time of the main data release. So the second slide here is the data that was put out in November and subsequently presented at multiple medical conferences. This is the six-month interim data with LUM-201 on three different doses and a control. So the four columns on the left are the AHV values for each of the four arms. At the time of the interim analysis, the 1.6 mg arm showed 8.6 centimeters in AHV, and the active control arm showed a somewhat anomalous value, and we'll talk about that in our discussion, of 11.1 centimeters. Remember, these are moderate PGHD patients, and in order to qualify for the trial, patients had to show greater than five nanograms per ml of circulating growth hormone on a stim test. This stim test is the same test that's used more broadly in diagnosis, where less than 10 nanograms per ml is considered to be growth hormone deficient, although we can talk about that and the various cutoffs as well. Except for in this study, or instead of using arginine or clonidine as the stim, they use LUM-201. So it's a great way to enrich for responders and also to ensure that they're not enrolling severely deficient patients. The four columns on the right show the historical results from four different large databases. These are for moderate PGHD patients. So if you look at the labels for some of the approvals of the more long-acting drugs, you'll see higher numbers here. So the important point is that from these very large databases, these are in moderate PGHD patients after being treated for recombinant growth hormone for 6 months in that first of the four columns and 12 months in the other three of those columns. You see the average very consistently right around that 8.3-8.8 cm. This is the same range on the left at the interim results, showing 8.6 in that 1.6 mg arm, and what should be reasonable to expect from the final results after they're unblinded in Q4. Phase 3 would be next, obviously, would need to be powered appropriately once the right dose is chosen and would simply be a two-arm trial comparison of LUM-201 to injectable standard of care, with enough patients in each arm to support, in this case, for phase 3, a statistically significant and meaningful assessment of the non-inferiority margin. And that margin is expected to be similar to all the other studies in this field, somewhere between 1.8 and 2.0 centimeters. So hopefully that sets the stage for the discussion now. And Dewey, we can take down the slides. I'm going to start by asking each of the KOLs to introduce themselves... their affiliation and a little background on how much of their practice is dedicated to treating PGHD rather than having me butcher their bios. I'm going to go around, ask each series of questions, which should take the first hour, and we'll spend the final 30 minutes taking questions, both live from the audience and in a written form. So you can start thinking now about what you'd like to ask. Just type it into your dialogue box on your Zoom interface. I'm the only one that can see the questions, so I won't announce your name unless you want me to, so don't be afraid to ask whatever you want to. So with that, why don't we start off with some introductions and have Dr. Bhangu go first? Just introduce yourself, your affiliation, and what makes you tick in the morning. Hi, good morning. My name is Amrit Bhangu, and I'm a pediatric endocrinologist in Children's Hospital Orange County in California. I'm also Associate Professor of Pediatrics in UC Irvine. My practice, actually, my duties are a mix of clinical duties, administrative, and research. In our practice, we see about 30-40 patients with stature issues. Not everybody is a, you know, a growth hormone deficiency, but I would say about another one third or one fourth of that slice of short stature we see is growth hormone deficiency. Yeah, looking forward to a nice discussion today. Great. Thanks. Dr. Olkser, why don't you go next? Yeah. Hi, I'm Erica Eugster. I'm a professor of pediatrics at Riley Hospital for Children in Indianapolis. I've been here for 26 years, came here straight out of fellowship, and think I have the best job I could possibly have here at Riley as a pediatric endocrinologist. I am a generalist. I do general endocrinology, meaning that I do as little diabetes as possible, and I see a large number of patients with concerns of growth. Looking forward to the discussion. Thank you. And Dr. Diaz. Yes, my name is Alejandro Diaz. I'm the chief of pediatric endocrinology here in Nicklaus Children's Hospital in Miami, and as an associate professor of pediatrics for Florida International University. Our practice, we are 10 members, 10 ped endos, and I do mainly growth and thyroid. We see, we do 1 to 2 stimulation tests every day and I'm also looking to go through this discussion. Thank you. Thank you. Dr. Misra? I am Madhu Misra. I'm the chief of the division of pediatric endocrine at Mass General Hospital, and the Todd Professor of Pediatrics at Harvard Medical School. Like Erica, I've been here for a long time. This is my 25th year at Mass General. I will be moving on to UVA shortly, but as of now and until November, I'm still here. I specialize in pituitary and bone disorders. And I would say that maybe about 5%-10% of my patient population probably has moderate growth hormone deficiency. Great. Dr. Reifsnyder. My name is Kent Reifsnyder. First, I want to welcome her to the state of Virginia, 'cause she'll be joining me here shortly. I am here at the Children's Hospital of King's Daughters in Norfolk, Virginia. I've been here for about 14 years. I'm an associate professor affiliated with the Eastern Virginia Medical School, and I do predominantly general pediatric endocrine, but I'm also the main researcher here at this institution, and have been involved in phase 2 and 3 studies over the last 8 to 10 years. My other background involves my affiliation with the Human Growth Foundation, and part of this is all due to my mentor, Steve Turner, second fleet back on jaw from Cincinnati Children's, where I performed my fellowship 15 years ago. All right. Thanks, everyone. Right. I'm going to start off talking about diagnoses and current treatment patterns with Dr. Bhangu. Can you give us a clinical definition for a diagnosis of PGHD, and are there severity subtypes that are used both during diagnosis and that you see in your practice? So, pediatric growth hormone deficiency typically presents as extreme short stature, which is height, usually is below the two standard deviations below the mean. And also it depends on the mid parental height or the parent's height is, so we all always have to correct for that. You always have to look at how the growth is, especially over the last year, and if so, even the last two years are also important to how the growth has been. And there are some typical, classical features of growth hormone deficiency. So not only it causes slowdown in height, you would see increase in weight and, you know, the BMI goes up, and, you know, the height is not going up. So there are some other classical features that are associated with classical growth hormone deficiency. But as far as the severity of the growth hormone deficiency, as described by the stimulation test, that's not very concrete. It's not been, you know, well described or, you know, used in clinical practice that much. And also, in my clinical practice, we usually do not go by mild, moderate, or severe growth hormone deficiency. If the growth hormone values are below a level of 10, for example, on a stimulation test that you mentioned in the introduction, that would be considered to be a growth hormone deficiency, and then treatment is pursued for these patients. Great. Thank you. Dr. Eugster, am I pronouncing that correctly? I want to make sure I get it correct or- That was perfect, Corey. Thank you. The typical patient, how do they find their way to you? Are they referred from a pediatrician, or do you take self-referrals? Before that referral, what types of basic laboratory and imaging tests are performed, if any, and how many do you need to redo? Yeah. So we do require a referral, and we have a huge referral base. We have a referral base of over 5 million. We get a tremendous number of referrals every day because we are essentially the only children's hospital in the state of Indiana, to speak of. So we also get referrals from a huge range of providers, not only pediatricians, but many, many, many physician extenders, such as nurse practitioners, physician assistants, also family physicians, so, you name it. And unfortunately, I would say the norm is that often tests are done that are not indicated, and the tests that are indicated are not done prior to the referral, so the kids end up having to be poked twice. Our strong preference would be to have no tests done, to just have the physicians and the other providers refer the patients and let us do the workup based on our history and physical exam. In addition, often they will obtain, for example, a bone age X-ray. While we read all of our own bone ages, we do not rely on the radiologists. In fact, we did a study where we found that we disagreed with them 68% of the time. Unfortunately, this then requires us having the bone age done elsewhere, pushed to the cloud so that we can access it remotely, and takes often a large amount of time on the phone with our MAs trying to reach the other facility to get the bone age uploaded to the cloud. So it's not perfect, but that's sort of the day-to-day. Dr. Diaz, during this diagnosis process, and even after treatment starts, how often are you testing for IGF-1 and for stimulated growth hormone levels? And also, kind of set the stage for the audience, just as a reminder, why we should and need to do that. And then after the diagnosis, how do you decide on a treatment option, and does this severity of PGHD play a role in your selection of options? The important thing for me is that I live in Miami, and in Miami, everyone wants to be tall. Most of the patients I see in my office are not short. They usually are late bloomers, or they have familial short stature, and those are by far the most common causes of short stature. However, no one wants to pay for growth hormone treatment, and growth hormone is expensive. Then, when I see a child on the short side of the normal range, I always order labs. In those labs, I include IGF-1. IGF-1 is a marker of growth hormone production, and it's not so sensitive or specific, but it's the only way to do a random test to have an idea of the growth hormone production. I do IGF-1, IGFBP-3, and I have a panel of labs that I do. When the child is shorter than expected, and the IGF-1 is less than minus one standard deviation below the mean, that's when I decide to do growth hormone stimulation test. Most of the time, I do the growth hormone test, just to be able to get the growth hormone paid by insurance, because it's expensive. Then, I do clonidine and glucagon the same day. The normal value is more than 10, but we know that more than 7 or more than 5, indeed, can be considered normal. It's a tricky part, but to the point that I only do MRI of the brain when the level is less than 7 or 8 or 5. But, again, growth hormone deficiency happens in 1 in 4,000 to 1 in 10,000 children. Therefore, if someone is below the 5th percentile, only 1 out of 200 to 1 out of 500 going to be deficient. And therefore, I treat, I would say 90% of the kids I treat with growth hormone are not deficient. And, when I find someone who is deficient, usually we know the child has a problem when they open the door, when we see them the first time. They have some features that are characteristic, and we look at the growth chart. Also, the growth chart is telling us that the child has a problem. And in those cases, I order a lower dose of growth hormone. I usually order 0.2 milligrams per kilo per week. I start half the dose for a week. This is something that I do, just because sometimes they develop pseudotumor cerebri, headaches, and ideally, doing a lower dose for a week, it may do a difference, and I don't have a way to prove that, but that's more or less what I do. Those kids who have normal, more than 5, more than 4, or I think they are normal, they have normal growth hormone production or very mild, I do 0.3 milligrams per kilo per week, and more or less, that's my modus operandi. Thank you. Dr. Misra, given that all of these are injectables right now, this question kind of gets to how much resistance is there to the injections, and if you had an oral option, all else being equal, how much easier would it be to convince your patients to start treatment, and how would this influence your practice? Yeah, so that I think is the easiest question thus far. And if there is an oral option to an injectable option, I'm sure that's going to influence factors greatly. So most of my patients, when they're coming to see me, are either not aware that growth hormone is given as an injection or that it's given usually as a daily injection, although we have the weekly long-acting preparations now becoming more available. When they hear, and this is. I'm talking about after they realize that they need to be on growth hormone because of the stimulation tests that have been described already. When they realize that this could be an injection, that this is an injection, that the majority, I would say, are not, not super happy about this. I would say about 20% of my patients are really unhappy about the injectables. And, having said that, you know, because we do not have an oral option thus far, most of the patients will come around to the idea of getting the daily shots and will, you know, we, we'll get started on the daily injections. So that's the beginning of a treatment. Now, there is an issue with adherence to growth hormone injections, and when you look at the data out there, it appears that. And again, the data are very, very variable. There are some studies that have shown that adherence can be 75%-95% of the time. There are other papers that show that adherence ranges between 5%-85% of the time. There certainly appears to be enough data to show that about two-thirds of the patients will miss at least 1-2 injections a week. And this relates to the inconvenience of injections as well as the pain of injections. Self-administration is a problem also when it comes to our teenagers and at least the older children that can get their injections themselves. There are issues with the device and so on, so and also more recently, they've been issues with just availability of the injectables. So all of this does lead to reduced adherence, and I suspect that with oral growth hormone, an oral option that is going to be less of an issue. If safety, efficacy, and cost were all equivalent, then I think it would be the easiest thing in the world for patients to prefer an oral version to an injectable version. Dr. Reifsnyder, so this idea of different sub classifications of PGHD, do you use those during diagnosis, if at all? But where this question is really going is, even if they're not formally placed in one of those types of categories, mild, moderate, severe, do you see differences in those patients' responsiveness to growth hormone? And second part of that question, or third part, is differences to their responsiveness to growth hormone over time. So I think those are all really good questions, because I think some of the families, as like my colleagues have alluded to, although I introduced the idea right before I do the stimulation test, that, hey, the therapy is a nightly injectable, and of course, they're a little apprehensive about the idea. But once we reach the threshold that they have confirmed growth hormone deficiency, I don't know if I would necessarily say I subdivide them or there's not literature out there. But personally speaking, I do kind of subdivide them in response to the question that the parents also often ask: Well, how much of a response will I see, and how quickly will I see? And so I use the stimulation test response to try to help gauge that question or answer that question as best as possible. My personal experience is that the more deficient you fail the test, it's inversely related to sensitivity. So if you fail the test significantly, as my colleague in Miami referenced, you can use lower doses and not only use lower doses, but have a very profound, robust response. Conversely, if they kind of have a subpar or what I would describe as an insufficiency rather than deficiency, it does seem that their response is a little less, and they may even need a little bit more therapy. So that's how I kind of approach the question by the families as to what to expect. Now, having said that, all of the categories tend to have a better response in the first year, 12- 18 months, and then there's almost like a plateauing effect, where they kind of normalize to their age and gender specific pre- or peripubertal, depending on which group they're falling in, normal growth velocities. For the first year, year and a half is a very robust, almost what we call a catch-up response. And the younger you are also plays a role. A young toddler child, preschool-aged kid does grow a little bit faster, both the normal individual and the one who's treated with nightly therapy than does, say, a 10-year-old. And then conversely, a peripubertal kid also grows faster than the kind of the mid-range individuals. Yeah, somewhat paradoxical, but it's a point that we're going to come back to and emphasize. Because I think it's an important point that the audience might not be super aware of. I'm going to go to Dr. We'll start next, and we will come to talk about the long-actings in a second. But in thinking about the daily injectables that have been on the market and available for 38 years, other than the obvious, that it's a daily injection, are there other shortcomings, not just from this therapy, but just in general, what do you monitor for some concerns when you're following a child that may be problems on the safety side related to the drug? Yeah. So I think, you know, growth hormone is extraordinarily safe, and we have an incredible amount of data. I often tell families: We probably know more about growth hormone than almost any other medication that we prescribe because of the large databases, but there are probably tens of thousands of children receiving growth hormone therapy. That being said, there are a huge number of headaches associated with treating children with daily growth hormone. As has already been alluded to, you know, a substantial number of children do complain of pain with the injections. All the different growth hormones come with different bells and whistles and different types of devices that don't all function as well as they, as one would hope. There's a huge issue with insurance companies changing which growth hormone is approved on their formulary. Sometimes this happens to a single family two or three times a year, and every time it happens, there has to be a new prior authorization, a new, you know, file that contains reams and reams of paper documents, copies of clinic visits, et cetera. Families just feel that they get jerked around, no end by this. As you all know, and has also been alluded to already, there's a national shortage right now of growth hormone, in particular, the three most widely prescribed forms of growth hormone. So insurance companies won't even allow us to prescribe the few growth hormone types of growth hormone that we can get that are available because they say it's not on their formulary. So that and then some of the growth hormones need to be refrigerated, others don't, and so this affects certain families and their particular lifestyle and specifications. Again, families are just sort of caught in this quagmire, and are, you know, very, very upset, understandably. As far as what else I monitor, so by definition, children with growth hormone deficiency are at risk for additional pituitary hormone deficiencies. So I check thyroid function studies annually, and I also check IGF-1, just to make sure that it is not, you know, extraordinarily high. If it is high, I will likely hold the dose at the next visit. I think in terms of safety, you know, we do go through a short list of side effects that have been reported, but I also tell families that these are all extremely rare. Many of them I've not ever seen. So it is a very, very safe drug. But again, I think we do worry about the very, very, very long-term potential adverse effects of supraphysiologic growth hormone, for many decades, going forward, and those data we really just do not have at this point in time. Great. Thank you. All right. supraphysiological high levels of growth hormone. We'll come back to that one, too. But, I'm going to ask both Dr. Bhangu and, and Diaz the same question, and that's concerning SKYTROFA. Now that it's been out there for almost a year and a half, why do you think that more people are not being put on SKYTROFA? And right now, are you seeing more comfort, better reimbursement, such that this could end up being the dominant product in, in three years? Dr. Bhangu, why don't you start? Yeah. So we have, so alluding to, the growth hormone shortage, which started last year, it started with, Norditropin, then Genotropin, and then, another brand. So we started to, convert, I would say, a lot of patients from daily growth hormone therapy to weekly growth hormone therapy. But what has happened is, our staff has gone through a lot in the last one year. There's been a lot of, burnout and turnover in our staff, which handles growth hormone prescriptions. And, I, especially in our group, is very cognizant of that fact. Even with daily growth hormone, there's back and forth. Insurance denies, the growth hormones which are available, which are not on their formulary, or they are not on contract. So to save, angst that our staff have to go through, I personally and some of my colleagues have not really started many patients on the weekly growth hormone that we thought or we expected that we would. So that, that's the reason why, we did not, start a large amount of patients or converted a large amount of patients to weekly therapy. Even though in California, especially in our county, the Medicaid, which is also called the Medi-Cal over here in California, approved, weekly growth hormone therapy, but we have been very, cognizant of that fact and very, I would say, careful about transitioning patients over to weekly growth hormone therapy. Of the ones that I have, switched over and I've seen them back in my clinic, are the patients with SKYTROFA. What I've noticed is, the efficacy is good on it. It's really good. Children grow very well on SKYTROFA, but they also tend to have very high IGF-1 levels. I had one patient who had very severe body ache and headaches that I had to switch back to daily growth hormone therapy because they were doing very well on growth hormone therapy, and parents said: "No way we're going to do the weekly." And then I had another patient who on day six. So, we have to monitor IGF-1 levels, and we just talked about the supraphysiological levels of growth hormone, but also IGF-1 levels. We do not know what these do over the long term and also with the acute effects, the acute, you know, short-term side effects. We don't know what IGF-I levels do, but one of the goals of the therapy is to keep the IGF-I levels within the two standard deviations above the mean. And with the weekly growth hormone, when we monitor IGF-I levels, we try to do it on day 4 or 5, but sometimes patients do it, you know, the next day, the second day after growth hormone therapy. I had one patient who did IGF-I on day 6, and it was, you know, at three standard deviations above the mean. So even on the prescri... So what you end up doing is, you're scrambling to lower their dose very quickly, and then you realize you have to get another authorization. So you end up because it's a different pen, you know, so SKYTROFA comes in, you know, different strengths. So it's actually leading to more paperwork. Not going too much into that. Another side effect that I do want to mention with the weekly, where we have to be very careful, is it causes very severe lipoatrophy. Because especially if patients are not moving their sites around, they really have to move all, at least six or eight locations. If they're not moving the sites around once weekly, cause and they're only changing two sites, causes very severe lipoatrophy. I've seen at least already a couple of patients. Then the second one is the one which is available now is Sogroya. I've written for that, but I haven't seen any patients back. The data from the clinical trials suggest that the IGF-1 levels are not very high with Sogroya, and also they have a very good growth velocity. I don't have any experience with that yet. Great. Dr. Diaz, your thoughts on the same topic? I have the same experience like Andre. I order when SKYTROFA came out. I like the data. I mean, it appeared to be impressive. I would have concerns about the IGF-1, though the studies, initial studies showed them significantly higher than normal. They say they go up in 48 hours, 72 hours, they start coming down. However, the experience is that one that we see high levels of IGF-1, but for me, the priority, we're a very busy practice, is to be efficient and to be functional. And SKYTROFA was not covered by the insurance. They gave some interim medication, but the process was painful because we needed to do appeals and to do a lot of work. And basically, I can't afford to go through that with the personnel I have in my office. Because I have bad experience with the first patients I started on SKYTROFA, we decided not to do it anymore. And again, the concern about the IGF-1 is another one, but, I, what I want is to work and to get it. That's my goal in medications. I, I want to the medication to be. The patient to have access to the medication, in an efficient manner, and it didn't work. Dr. Misra, if you had any thoughts on that same topic, but then I'll expand the question now that we've got the two other long-acting growth hormones out there that Dr. Diaz just referred to with Novo Sogroya, that was approved at the end of April, and now just starting to be available, and Pfizer's NGENLA, NGENLA, sorry, I knew I was going to mispronounce that. NGENLA, that was approved at the end of June, but I don't think it's available yet. So within your practice, do you see now having three long-actings available, bringing in new patients? Or are you just, if you use them, going to end up taking share from the daily injectables? Great question. So I really think that these new growth hormone preparations are going to mostly take the share of the daily injectables. We haven't really had much of an issue with getting insurance approval for growth hormone deficiency. The areas where we do not get approval from insurance are often in the realm of small for gestational age or ISS. So those are different indications. But as far as growth hormone deficiency is concerned, for the most part, almost always, we will get approval from insurance companies, and patients do get started on growth hormone, even if they dislike the injectables. So I personally do think that as these preparations become more popular, that they mostly will be taking the share of the daily injectables. We haven't started using these long-acting growth hormone injections much. We do have a handful of patients on SKYTROFA. I have actually seen one patient that developed a lipoatrophy, like Dipankar had mentioned, and I do worry a lot about the IGF-1 levels. I also worry about the sustained high levels of IGF-1 over time. You know, notwithstanding the fact that the levels do come back after day two to lower levels, it still is worrisome that the levels are high for a period of time, longer than they would be with daily growth hormone injections. The other issue that has not been borne out so much, but is a concern that and that many of us have shared is that if somebody were to develop pseudotumor cerebri or hyperglycemia with growth hormone, with a long-acting growth hormone, you just can't take it away right away because you still have the weeks left of supply to get through. Right? So, that's an issue. So, you know, we haven't started to use it as much for those reasons, but also because, you know, we have one prior authorization specialist, and she's really swamped with the daily growth hormone prior authorizations at this point of time and the many changes that are having to happen because of the shortage of some of the preparations. We just haven't wanted to give her, you know, yet another set of prior authorizations to deal with. Is the lipoatrophy right at the site of the injection, or is it a more generalized effect? At the site of injection. Interesting. All right. Dr. Reifsnyder, so we've got all three of these long-acting entrants. They each have a slightly different mechanism of action, but they all accomplish the same thing, right? High levels of growth hormone that are sustained, leading to higher levels of sustained IGF-1. So the question to you is the same thing. I mean, do you have concerns a priority in the lack of with the lack of long-term data about these kids persistently being exposed to these high concentrations? I do. I think that that's why it's so critical that there is ongoing phase four or registries or some type of safety data collection, just as, you know, you stated 30 years ago, when Norditropin came out, more than 30 years ago, about 25 years ago, was when our Protropin came out. We had the same concerns, right? We were worried about acute and long-term side effects, and we've had a lot of data to show that Norditropin is very safe. I even use it in my cancer survivor patient population. It's that safe. But with the long-acting, that is a major concern. I think we all have the same concerns, that sustained high levels IGF, what does that mean? Is there a short-term and/or a long-term price paid? So these individuals certainly warrant more follow-up, closer follow-up and more surveillance. At least that's my standard of care. I do have about, well, 18 on SKYTROFA. It works well, but you have to use lower than what's recommended because it works so well, and I think the IGF-1 levels are a little higher than I'm comfortable with. Great. Thank you. All right. I want to switch gears now and talk a little bit about Lumos's LUM-201, set the stage for the data coming in Q4 later this year. Dr. Misra, in looking at the historical clinical trials with growth hormone, I didn't show an effect going from 6 months to 12 months to 18 months, but we asked a question about it earlier, and I want to get into this a little bit more. What happens to those AHV rates at each of the time points, specifically for more moderately deficient subjects? And how does that compare to the more severely deficient subjects? So, generally, we think about children having a genetically predetermined trajectory for growth that they will follow, over time. And so the further they fall from that trajectory as a consequence of growth hormone deficiency, the more rapid the initial response will be to growth hormone therapy. And we typically think about the growth velocity being the highest in the first several months to a year of giving growth hormone, and after that, the growth velocity decreases over time in subsequent years. So generally, because of this, predetermined genetic trajectory and the fact that the further you fall, the more rapid your catch-up is, the rate of growth tends to be more robust with more severe growth hormone deficiency. And it also depends upon the age of the child. So the younger the age, the more rapid will be the catch-up, and the greater is that annualized growth velocity at the beginning or even subsequently. So I hope that answers the question. So usually I think about growth velocity being the highest earlier on in the course of treatment, and it kind of decreases in subsequent years. And it is highest, higher when there is more severe growth hormone deficiency and with younger age, younger bone age, and also with the higher dose. Yeah. No, that answers the question. I think it's worth really repeating because it's not obvious for those of us that don't do this day in and day out. Dr. Diaz, I wanted to ask you next, and Dewey, if you could put those slides back up again for a second, just the second slide with the data on it. And the question is: Do you think that that expected average height velocity in that 8.0-8.6 centimeters is similar to what you've seen for injectable growth hormone in your more moderate patients in your practice? Yes, I had very variable results. In general, as I mentioned, I would say 90% of my patients don't have growth hormone deficiency, real one. They may have mild forms, but there are some markers that help me to find out who's going to respond, and the easiest one is usually the IGF-1. When I see the IGF-1 on the lower range of the normal range or slightly lower than the normal range, those patients usually have that response that we see, that the first six months, one year are impressive, and then they kind of plateau, but still growing a little bit faster than normal. However, those kids who have a normal IGF-1, usually more than above the mean, their response to growth hormone is not as good. Some of them, when they have the IGF-1 plus one, or they usually don't respond quite well. I mean, it's variable. I use a lot of growth hormone. I try to avoid using as much growth hormone as I would like to do, but I mean, again, it's Miami, and we have a Latino population. Some of them tend to be short. But I learn more or less who's going to respond or not to the treatment, and based on that, the response is variable. Most of them have some improvement, but the IGF-1 is, in my opinion, the best marker to have an idea. And I hope, I mean, if Lumos works, I mean, this is the perfect situation here. This is something that I've been talking for years, right? To do something that is less invasive, that daily injections for these kids who are on the lower side of the normal range and want to be taller. Great. Kent, I'm going to leave those data slides up, and I know you weren't involved specifically in this trial, so hopefully you can answer this. But looking at that 11.1 AHV growth rate in the control arm, we know that there were 2 young subjects in there that were outliers, that grew around 15 centimeters. That helped skew that average. You know, when you have low numbers, that has a big impact. But do you have thoughts on how big an outlier that growth rate is? I mean, do you ever see kids that grow that quickly in response to recombinant growth hormone? So I think you bring up some great points, Corey. I think that first and foremost, the power is not there, right? It's only 10 subjects, and so 2 of the 10 or 20% of them had a far above and beyond what we normally see in clinical practice. So I would say that in the context of remembering, the more deficient you are, the more sensitive and more robust response you have. So that's one thing. And then secondly, the younger kids grow faster, either non-deficient kids or therapeutically treated kids, they grow faster than the middle group kids. So I kind of categorize like preschool, then school-aged kids, and then pubertal kids. Those are the three kind of buckets of kids, and they grow differently. And so those two were preschool kids, so they inherently grow faster than the other buckets. Well, the middle-age group, not as fast as the peripubertal kids. Two, I think that I don't know how deficient they were. I know that these were all moderate deficient, so they kind of fell in that moderate, but maybe they're on the lower end of the moderate, and so therefore, they were more sensitive. But, fifteen centimeters per year is very, very robust. I rarely. If I saw that individual at a follow-up at four months, and the annualized speed was 15 centimeters per year, I would absolutely be checking labs and also wonder, as some of my colleagues mentioned, that maybe either my dose is too much or they're not using the delivery pen properly, and they're mistakenly getting higher doses than anticipated, thus yielding a very, very atypical response. Thank you for that. Erica, I'll ask you next, and so I'm going to leave the slide up and just refer those slides and refer back to this one, that profile for the PK of normal growth hormone in that yellow box. Do you believe that 201, because of the mechanism, has the potential to restore a more normal growth to these kids? And implicit in that question is whether or not you and other physicians are going to care that it has this profile and that recombinant can induce a super physiological growth because of not having that pulsatile release. Yeah. So I think it's just inherently very attractive to have something that simulates normal physiology. And I think for pediatric endocrinologists, we always have a bias toward getting as close as possible to normal physiology because mother nature didn't, you know, evolve the way she did by coincidence. There's a reason why the body works the way it does. Same for all hormones. If we can have endogenous hormone production rather than, you know, giving hormones, it's always going to be far superior. So I think this is one of the most exciting and positive things about LUM-201. And again, getting back to the issue of safety, getting back to the issue of long-term effect of very high IGF-1 levels, I think that LUM-201 really is, is in a different class altogether because it appears that it would be much less likely to have very high IGF-1 levels. And, you know, getting, getting back to the whole discussion about, you know, catch-up growth, I mean, that, that all happens for a reason. It happens. You know, because as Dr. Misra mentioned, and several others, you know, every child has a set point for growth. And if you look at a growth chart, it's just beautiful. I point this out to my trainees all the time, that despite the same, you know, milligrams per kilo per week of growth hormone, what a child will do is cross channels and zoom up to a particular percentile and then grow parallel along that percentile, because that is where they are destined to grow. So I always tell families, our goal with therapy is to allow your child to fulfill their genetic potential for growth. I'm not trying to make them any taller than they would otherwise have been. And I think the whole mechanism of action here is a strong positive. That's a great point. Okay. Dewey, we can take the slides down now. Dr. Bhangu, I don't have a slide for this, but I know you've taken a quick look at the IGF profile for the LUM-201 from their interim phase 2 results. And just in general, can you comment on the, the safety profile, specifically with respect to IGF-1, and tie that into the mechanism for 201 that allows for more normal feedback inhibition? Yeah, I have looked at the IGF-1 levels on the two doses which were used, and that was the 1.6 milligrams, and the other one was the 2.3 milligrams. And the IGF-1 levels on both of these, before and after the treatment, both in terms of absolute IGF-1 and IGF-1 standard deviation scores, significantly improve after six months of treatment. And they seem to have gone up by at least one standard deviation on the 1.6 milligram dose and around approximately 1.5 standard deviation change with the 3.2 milligram dose, which is. And also important to note, although a small number of patients, it does not seem like these patients have super physiological IGF-1 levels from the phase 2 data that we have. So it seems like it's very safe, but you know, safety then again will be more importantly you know studied in the phase three trials as well. Great. Thanks. Okay, I'm keeping an eye on the clock, and I want to make sure we get time for questions from the audience. So I'm going to ask one more round of questions from each of the, the panelists and then go to the audience. Kent, I think you said earlier you have about 18 patients that are on SKYTROFA now, but as a percentage, you know, what percentage is that roughly? And where do you expect that to be in three years? Is this something that you would expect you would take to a very high percentage, or are the daily injectables always going to have a place in your practice? That's a great but very difficult question. In part, as many of the colleagues already alluded to, what has made this such a challenge for us for the last 9-12 months is the shortage. And so we're often having to bounce around to try to find what we can and grab it when we can, and that leads to a lot of angst and paperwork, both on the family's behalf and our staff's behalf. As a consequence, SKYTROFA, because they have an abundant supply, they've been able to kind of take advantage of that opportunity. And so I would say I have about, I don't know, 10% of my patients on SKYTROFA, because they're able to take advantage of the shortage and use that as an approval process. I don't know if that's sustained. That will be based on one of the biggest barriers we have is insurance, what they're willing to pay for, what they approve and pay for. That's what dictates almost all of our options, unfortunately. We may have a preference for a particular product, but at the end of the day, insurance and the policies the families have really dictate which choices we use. Does that answer your question? Yeah, it does. It's nobody's got a crystal ball, but it, it helps qualitatively. Dr. Diaz, what percentage of your patients now would you categorize as having that moderate GHD? I get that it's somewhat of a artificial label that we're using because of the, the nature of the mechanism for LUM-201, but what we're trying to get at is, what segment of the population would 201 be A, appropriate for? And remember I said at the beginning that the stim test with 201 had to be above 5 nanograms per ml, but that equates to 3 nanograms per ml on a standard stim test. Yes, I would say that 90% of our patients have more than than 3 nanograms per milliliter. I would say more than 70% of our patients have more than 5. As I mentioned before, those patients who have real growth hormone deficiency, you see them quite straightforward, and also the growth chart helps you a lot. But, most of the patients that we see here in our practice are moderate or mild hormone deficient. I'm going to jump to Erica for a second. If you had an oral drug that did show non-inferiority statistically to daily growth hormone, but it was therefore met the criteria for FDA approval and was approved, but it was consistently, say, 1 centimeter less. All else being equal in terms of safety, how widely would you expect to use it in your practice in this moderate PGHD population? Yeah, a centimeter difference in height would not bother me in the least. The safety and the physiologic mechanism of action would trump, easily trump a centimeter. And we know, we know from a lot of studies, right, that height does not dictate success or happiness, and that children's quality of life is equally good if they happen to be short. So, I personally am very conservative, and to me, that would absolutely not be a problem. The growth. I'm sorry, that excludes people from Miami. So I gather, Alejandro, and I feel bad for you because that's tough. And we see, we see a lot of Burmese patients, a lot of Hispanic patients that are referred for short stature, and they're absolutely normal for their families, and I don't treat them, but I'm in Indiana, so. I know, I know. But Miami is very peculiar. I'm only five feet tall, so you know, hey, some families say that means I'm not qualified, but I beg to disagree. It's a mixed bag. Yes. Dr. Misra, may I ask you the exact same question? You know, if you had LUM-201 with the profile as posed here, how compelling do you see that? You know, I really like the more physiological aspect to how it stimulates growth hormone secretion and the pulsatile secretion of growth hormone that it results, and it's really very attractive. I also like the fact that when you have that feedback loop in place, potentially the autoregulation will prevent very high IGF-I levels and will allow for some maintenance of, you know, safe IGF-I. So I think it's very compelling. Dr. Bhangu, a final question before we go to questions from the audience regarding the types of doctors that treat this disorder in the future. If, do you ever see pediatricians getting involved, given that they're kind of the first line of contact? And if we had an oral option, is this something they could ever treat, or is it always going to stay with the endos? No. Pediatricians do not treat growth hormone deficiency or short stature. If they would, then we would not get so many referrals, like, just like Dr. Diaz said. But here's the thing: You know, we started thinking about pediatricians using specialized endocrine medications when Ozempic and especially when Wegovy came out, we thought some of the community pediatricians are going to be really hands-on, and they really don't want to do it because they realize there's so much paperwork, authorization, and they need to hire extra people on the staff. So they push that to the pediatric endocrinologist. Also in the past, many pediatric nephrologists used to use growth hormone for renal failure, short stature, and at least in our practice and the places I've worked, there's, you know, also, that's also in the realm of a pediatric endocrinologist now. There are other growth-promoting medications. We're not talking about growth hormone, which geneticists used to see, for example, achondroplasia, and we are the pediatric endocrinologists also starting to take care of patients with achondroplasia because of the same reasons. You know, the staff is not experienced to handle these authorizations and paperwork, you know, that endocrinology offices are. Great. Thank you, Dr. Bhangu. Okay, Sarah, why don't we get a question from the audience, and we'll take some orally first? Great. Thank you, Corey. Please hold for a brief moment while we pull for questions. So our first question comes from Charles Duncan from Cantor Fitzgerald. Please go ahead, Charles. Hi. Yeah, thanks for taking the questions. And Corey, really great set of questions, very nicely sequenced. Thanks for hosting this call. I had a couple of questions that were, you know, really quite similar to a few of those that you asked. The first is for Dr. Bhangu. He mentioned early on in the call regarding this stimulation test, said he doesn't use it or doesn't really consider patients mild, moderate, or severe. And I guess I'm wondering if you had a drug like this one, like LUM-201, that may work best in a moderate patient, would you start to incorporate a stimulation test, and would you start to kind of classify your patients differently as mild, moderate, severe? Yes. So, the patients that we are serious, that they have clinical criteria for growth hormone deficiency, and we want to treat them, we do do the stimulation test, and there are many different agents. But in clinical practice at least, we don't look at the severity, just like you've said. But yeah, if there is a specific FDA indication for, for example, for LUM-201, an oral product which is approved for moderate, I think, you know, the community of pediatric endocrinologists will start to look at it, and perhaps also treat differently. Yes, so the data is there, but we, there is an easy transition and a possibility to look at the data differently. Okay. And then my second question is for any one of the KOLs, and you've all been very helpful. Really appreciate your perspectives. But when you think about the target product profile, as Corey mentioned towards the end, it was non-inferior. It seems to work well in certain patient population. How would you sequence the use of it? What would be the biggest determinant? And let's forget about whether or not it's paid. Let's assume that it's reimbursed. So what is it in the clinical data that you'd like to see? And how would you sequence LUM-201 versus the daily injectables or the long-acting? I think I can go first. Sorry, go ahead. I was just going to say that it's. I'm sorry, Corey? I was going to say, why don't we hear from everyone on that answer? But go ahead, Dr. Misra. No, I was just going to say that the fact that this, that this is an oral preparation versus an injectable preparation is, is a big deal. I think that's going to be a major driver of decisions. You know, for an indication where this would be a logical choice. I think it's a no-brainer that any child or parent would prefer an oral preparation to an injectable preparation, with everything else being the same. Makes sense. I agree. This is a pediatric population we're talking about, and by definition, that is a huge advantage. Any dissent? No. if inferiority, if there is no inferiority, significant inferiority, and it's safe, for me, safety is very important, then oral is a win-win situation. This is Kent. I would agree, having been the one who uses probably more SKYTROFA than many others on this call. My big concern is long-term high levels of IGF-1. This oral agent, should it continue to show non-inferiority and the power, you know, in the phase three, you build up the subject power to support its efficacy. The fact that it reproduces normal physiology is resoundingly just our goal in life. As Dr. Eugster stated, "If I can put back what was supposed to be there in the exact same profile, that's a home run. The only situation where I might be hesitant to use it would be if there are any structural problems in the pituitary gland or if there, you know, there's been radiation or something like that, where I know that the pituitary's ability to secrete growth hormone is going to be impacted or the hypothalamus is not going to be making GHRH effectively. Then I might be more hesitant about giving this medication, even though early on there might be evidence of moderate deficiency as opposed to severe deficiency. I would say that really gets to how imperfect the whole concept of growth hormone stimulation testing is. We know that it's not a perfect test by any means. So I think you would have to see how patients respond and keep an open mind that they may not all respond as we would expect. I agree with all of my colleagues, but I would say I would look at the long-term data with LUM-201. You know, what the drug does in a year 2, year 3 of therapy. So that will be, you know, I will, I will decide looking at after the long-term data, if this would be a completely a game changer. That makes sense. I have one last question, and then I'll hop back in the queue. I appreciate you taking all my questions, and that is for Dr. Misra. You mentioned early, early in the call, something about adherence, and I, I may have written it down wrong, but I think you said, you know, something on the order of a third of patients miss 1-2 injections per week. Is that, is that the real number? Did I write that down wrong? And that seems like a lot. So I guess my question is: how does that impact outcomes or, or even the duration of therapy on the daily injectable? It would seem to me that, that the patients need the drug in order for it to work, and per- and perhaps the pharmacoeconomic value of long-term dosing is, is really compromised by the lack of adherence. Thanks. I think that's a great point, and the number was actually even higher. All kinds of numbers out there in the literature, but the specific paper that I'm thinking about quoted a 60%, you know, occurrence of non-adherence in terms of missing one to two injections per week. So that was 60%, not even a third. You know, there definitely are data to indicate that if you miss, you know, one injection per week, you know, this is what the compromise is in terms of your height. Two injections, you know, so much, and three injections and so on. So certainly missing injections does have an impact if it's a consistent process on height potential. Got it. Thanks for taking my questions, Corey. Sure. Anybody else want to weigh in on any of that? This is Kent. I would weigh in that I think part of the non-compliance is, has been alluded to some of these products. One, the injection. The fact that you're giving an injection is a big barrier. Two, some of them require refrigeration. Three, with swapping in and out, I think knowing how to use the injectable device is a problem. And then lastly, some, at least here in Virginia, split households and/or travel burdens with families going afar for sports. It seems like sports has gotten pretty, pretty crazy now that they travel states away every weekend for games and so forth. I think all these things add to that significant non-compliance or suboptimal compliance that we all fight with. On a daily basis. And that's the appealing component to long-acting and this agent, quite honestly, 'cause it's easy to pack, you know, seven pills or three pills for the weekend. You know, that's, that's the easy thing to do. That's the appealing component of this, let alone the normal physiologic mechanism that seems to be in place. Yeah. I would just add parents turning over administration of growth hormone to their children, particularly the teenagers. I had an experience recently with a teenager where I told him that he was done growing. His growth velocity was less than 2 centimeters per year, and they... He and his dad kind of walked out of the room, and then they turned around, and they came back, and the dad was like, "Hey, Dr. Eugster, he has something to tell you." The child admitted that he had been missing a lot of his shots and actually did want to continue and wanted to be taller. So, we see that. I think that is not inconsequential by any means. Great. All right. Thanks, guys. Thanks, everyone. Tara? Yes. So the next question comes from Leland Gershell from Oppenheimer. Please go ahead, Leland. Oh, thanks, and thanks again to all the specialists for this very informative and educational discussion. A couple of questions from me. First, you know, as we contemplate the initial trajectory of LUM-201, you know, it's fairly easy for us to see you and your colleagues trialing this on new patients coming on therapy. But there are obviously many patients who are on injectables, whether, you know, daily or weekly. Would like to hear kind of what the barriers to be, or level of interest with respect to switching patients from injectables. Would it come down to, you know, those who may be having greater adherence issues? Would it be maybe more of a challenge, given that you'd have to sort of, you know, take them off what kind of currently has been working for them? How should we think about kind of the switch population? Maybe starting with Dr. Misra. Sure. So, you know, in our practice, we do try to make sure that our patients are well aware and informed about new products in the market and what their pros and cons may be. So we do discuss that with our patients. And, a lot of the decision making, most of the decision making is done in conjunction with, you know, the families. And so if the family and the child would feel that, hey, you know, this is a great option, even though I've been on growth hormone for a long time, and this is something I'd like to switch to, we would consider it. We would certainly consider it for the kids who have the poor adherence, the teenagers who travel a lot, you know, some of the other issues around adherence that have been brought up. So those would be absolute and, you know, situations where we would think about switching. If a child was doing very well on growth hormone injections and heard about this and said, "Hey, you know, I'm doing fine with the growth hormone injections as is, and I don't want to switch," I don't think we would push for a switch in those patients. There is a good analogy with the diabetes care. And when we have a new insulin, the patient is doing very well, we tend to measure the new insulin, but we don't push hard to make changes. Or we have the insulin pumps. I have kids that do great on multiple dose injections, then I don't push hard to do the pumps. But of course, it's a discussion that we have, and it's tailored to every patient to see what is more convenient of. At the end, the family is the one making the decision. Yeah. I would like to add, I completely agree with Dr. Misra and Dr. Diaz about the approach. If the patients are doing well, we tend not to switch. And also, patients also don't like to switch. And you, you would not believe it, even if they are on a weekly growth hormone, which is working for them, they would probably not want to switch, you know, especially if the families for which height is very important. Great. Thanks. Another question I have is with respect to safety. I mean, you know, clearly, growth. The point was raised earlier that growth hormone has such a long history of established safety over the years. And even though there, you know, we aren't seeing anything with respect to LUM-201 on the safety side, that would be concerning. Just wondering kind of what that comfort level is for the practitioner with a new therapy that's come out, that's oral, that works a bit differently, despite all the supportive data, if there's any cause for hesitation or any subset of patients for whom you may be more concerned about using this new agent. Yeah, well, I think, we'd have to acknowledge the fact that we don't have the years and years of experience, but I think, again, because of the mechanism of action of LUM-201, that inherently we, you know, if anything, feel that it was perhaps safer than daily injectable growth hormone. But this again, would be something to discuss with families, and I can see there being some families that would be reluctant to use it because it's a new product, and we don't have, extensive safety data. But I think, once we see, you know, the end of the phase two and a phase three study and, the safety data look reassuring, I think most pediatric endocrinologists would feel comfortable using it. Yeah, I would agree with Dr. Eugster because, we mostly think of safety issues being related to. But the safety issues that we're really worried about being related to IGF-1 levels. And, and therefore, you know, given that the IGF-1 levels seem to be reassuring with, 201, and also because of the normal, the more normal or physiological ways, it stimulates growth hormone secretion and that feedback loop being in place, you know, it does seem to be more reassuring. Yeah. I would also say I completely agree. But, you know, as discussed earlier on in the discussion, you know, in the presentation, the daily growth hormone is very safe. There's a lot of many years of data which shows that. I think mostly the safety concern we talked today is has to do with the weekly growth hormone preparations, which are out. So but it seems from the initial data that the LUM-201 is probably will be even more safer because of the very, you know, good IGF-1 profile, which tends not to exceed, you know, the standard deviations above the mean. And I would second or not second, I guess I'm the fourth to chime in. I would absolutely endorse that. I think that some families rightfully are apprehensive about trying anything that's new. There's just going to be a little reluctance to. And rightfully so. I feel like, I would be the same way because nightly's been around for 30 years. But if we're talking about new, comparing new agents to new agents, if everything else being even, if I had the choice between an oral that mimics normal physiology, and the levels are within the normal ranges as opposed to weekly, because both are essentially new items, I would choose the oral agent for a host of many of the reasons we've already discussed. I would go towards the oral agent over the weekly. Right. Great. And then lastly, just curious, you know, as we, you know, hearing this shortage of growth hormone that's been going on for some time now. Just wondering, you know, some of the, well, one of the companies in the industry has offered that, you know, the supply may be down because the existing daily companies are investing less, given their anticipation of the weeklies supplying, you know, increasing part of the market. I'm wondering if that's something that you've heard or if there are other drivers or reasons behind why there's been this growth hormone shortage. So one of the reasons that I've heard, there is a global increase in the global demand for growth hormone and, Norditropin and Novo Nordisk is a supplier not only for U.S., but global. So after the pandemic, there's been a global increase in growth hormone use, not just the U.S. And in other parts of the world. And apart from U.S. and Europe, other parts of the world have been using more growth hormone. So that's been the reason that I've been told about the shortage, which started with, Norditropin. I'm sure that one of the companies that makes growth hormone is also one of the manufacturers for the one of the GLP-1 receptor agonists that is being used to battle obesity. And so they have directed much of their resources to manufacturing this other product rather than growth hormone. That's what I heard. It was that the pen is now, was being rediverted to the GLP-I agonist, and so it was a pen shortage problem and not, not so much a growth hormone shortage. I confronted them, and they said that there is a plant in Denmark, the one that had the problem, that was new, and it couldn't work. Then they couldn't continue doing the growth hormone production. And it's severe, and it was far longer than they expected, but the pen theory is there also, and it's quite popular, and it makes sense also. Probably all the above. Great. Well, thank you. This has been very helpful. Thanks again. All right. Thanks, Leland. Thank you. We have a question from Yasmine Rahimi with Piper Sandler, but she couldn't be on the call, so she asked me to ask it for her. I can't remember who gave the number of about 90% earlier, but it was: What percent of your patients would you categorize as PIM positive with the Lumos criteria? And that would be greater than three nanograms per ml on a standard stim test, and yet less than ten. Everybody could just go around and kind of spitball a percentage. That's what she's getting at. Sorry, is the question like, how many% of growth hormone deficiency patients are moderate growth hormone deficiency? Yeah, that's a much simpler and straightforward way of stating. I haven't looked at my data, but I would think probably 60%-70% are moderate growth hormone deficiency. Very rarely we see less than 3 on the peak of the stimulation test. Yeah, I would agree with that percentage. Although at my institution, we use a peak of 5 as the definition of, you know, 5 or above your normal, because our assay changed several years ago, and what was previously 10 is now 5. So, you have to remember, when we talk about different cutoffs, that different institutions define these differently. But I would say 70% are moderate. Yeah, 70% for us. And be 5 adult. I would say the same in Eastern Virginia as well. In Miami, it's higher, because in Miami, people can. It's a cosmetic thing. Compliance in Miami is excellent because here, the social situation here is pathetic, and compliance is fantastic. Something that I tell them to do is if they forget one day, just add a little bit, 0.2 or 0.3 every day until they catch up. But compliance is not a problem here. It's a very, very interesting sociology in the city. And now that Messi is there, how. You know, that's called endocrinology, right? Co-cosmetology. Cosmetology. There is an interesting op-ed from Pediatrics years ago showing how. Yeah. Somebody that consumes 70% of the growth hormone, and people get upset, and they start fishing around, and, and then they know where to go to get it. Yep. Her second question was, what% of your PGHD patients are you enrolling into clinical trials right now on a monthly basis? I think she's trying to get at competition for enrollment when Lumos gets to phase three. Are any of you involved in any of these clinical studies? Yes. So, we are involved in clinical studies, you know, and we've been approached by other weekly growth hormone preparations for other indications as well. So as far as the number of enrollment in clinical trials, I would say it's usually not big numbers. I don't think enrollment in clinical trials is an issue, but. You know, every clinical trial has a set criteria, which is very strict, and you have to meet all those criteria. So in the end, not many patients get actually enrolled in the studies, but a lot of patients get pre-screened for eligibility, and there's a lot of patients out there which will be eligible for studies. I don't think there will be any shortage for patients for any clinical trials, if that's what was the intended question. Yes, it was. Anyone else, any different thoughts? Yeah, I would say we typically enroll, you know, one or two for these clinical trials, so it's a very small number of patients. Agreed. All right, great. Well, we still have a bunch more questions, but they're all pretty redundant with what's already been asked and answered. So, being efficient with everybody's time, if anyone, any of you five, any kind of closing remarks or observations or questions that were not asked that you anticipated, you would get asked and like to bring up now? Give you the floor. Given that this agent works from a physiological perspective, I almost wonder if this product could be used as a stim agent, too. As Dr. Eugster had alluded to, or outright stated, that stimulation test has limitations to it. It's not as accurate as we wish it to be. I almost wonder if this product in itself could be used as a diagnostic tool as well as a therapeutic tool. I think there are some data to suggest that it can be used as a stimulating agent. Yeah, that would be great! Right? But I don't know that we have any developed standards for how to, you know, define deficiency or such. Yeah. Almost like Macroorelin, right? And didn't you use LUM-201 for your own stimulation, or was that not the case? Yeah. No, it was the case. So for the phase 2, it's almost an enrichment procedure. In order to be included in that phase 2 study, all 82 patients needed to meet the criteria being over 5 nanograms per ml, as I mentioned, and that equates to 3 nanograms per ml on a standard stim test. So they've ensured that everybody enrolled in the trial is responsive, at least in that manner. There was a GHRH agent for adults, remember? I think, I think it's still available, no? For a stimulation test for adult patients. Yeah, it's called Macroorelin. Yes. Yeah. Kevin Ewing from Arizona. Yeah. But it was never approved for children, no? That's correct. I have a question. Is the growth hormone under the GHSR1a receptor the same as the ghrelin receptor? If you're asking me, I definitely do not know the answer to that. Okay. I'm wondering because I'm just wondering if there's an impact on appetite. Oh! In these kids. Yeah. Hmm. I think it's the same receptor, maybe different subtype of the same receptor. That's a great question. I wonder if they're following weight gain. They should be. Yeah, that's a great question. I believe they are, but I will get that answer. Thank you for the question. Anything else? Well, if not, I want to thank the audience for listening. If you have any questions for any of our panelists, you can come through me at cdavis@lifesciadvisors.com, or for Lumos, you can either get myself or Lisa Miller, that I believe all of you know. But on behalf of everyone at Life Sci and Lumos, thanks to the five of you for, I think, was an amazing discussion. We appreciate your time and your insights, and we'll have a replay of this that'll be available shortly on the Lumos website. Thank you.