Addressing Treatment Challenges in Growth Hormone Deficiency with Novel Long Acting Therapies. We welcome you all here to this event tonight. There are others who will be seeing this. We welcome those too who are watching the stream of this presentation. So welcome as well. I'm Larry Katznelson. I am from Stanford University School of Medicine. I'd like to introduce the speakers. First to my immediate right is Dr. Andy Hoffman, who is one of my colleagues at Stanford in the Division of Endocrinology as well. And to Andy's right is Dr. Sarah Duvall, who comes to us from the Pediatric Endocrinology Department at University of Washington, Seattle. So welcome to my two co-chairs, which is my co-speakers. Here's our disclosures for your review. The objectives of our program tonight are the following. As you can see, I'll read these. First is to understand how to apply the appropriate diagnostic test to the patient who has a high suspicion of growth hormone deficiency. The second is to evaluate the efficacy and safety of long acting growth hormone therapies in pediatric and adult patients with growth hormone deficiency. The third is to develop kind of a comprehensive treatment plan for patients with growth hormone deficiency, including the agent selection, dosing, and monitoring. And the fourth is to implement strategies to improve treatment, adherence, and transitions of care for patients with growth hormone deficiency. Now I'm gonna spend the next few minutes moving to more of a didactic conversation to discuss the basics for how to diagnose growth hormone deficiency. What I'm planning on doing here is reviewing the basic testing we have available. And you'll be hearing as the other speakers come up about certain applications that may be used from a pediatric standpoint and from an adult standpoint. So just a very basic figure that you've all seen many times in your careers, that growth hormone is produced by the anterior pituitary gland by the somatotroph cells under stimulation by growth hormone releasing hormone and simultaneous inhibition by somatostatin, resulting in a push-pull, if you will, and pulsatile release of growth hormone. Growth hormone levels during the day are usually quite low, with more release late at night. And based on this, a random growth hormone level for growth hormone deficiency is not useful. IGF-1, which is produced local in all tissues but also by the liver here, which flows systemically, is useful as an integrated marker for measurement of growth hormone reserve. IGF-1 levels in patients with a growth hormone deficiency are usually low, and I'm showing you here a pretty typical figure that demonstrates the change in IGF-1 levels with age. IGF-1 levels are low, and we always look at the results based upon age-specific norms, and they are low in most of the patients with growth hormone deficiency, but there's approximately 20% of patients who are growth hormone deficient as adults where the IGF-1 level is quote-unquote normal, usually in the lower end of normal, but it can be normal, and that's important. So a patient who has frank growth hormone deficiency may very well have an IGF-1 level that may be in the normal range but usually in the low end of normal if it is normal. There was a study done many years ago which demonstrated that in patients who have multiple axes knocked out of the pituitary hormones, that if they have multiple axes knocked out, at least three knocked out, the chances that patient is growth hormone deficient is very high, well above 99%. So the more tricky situations are those patients where there are no other axes deficient or one or two, but again, if the patient has at least three axes deficient of the pituitary gland, the chance that they're growth hormone deficient are really high, and one may not need stimulation testing to make a diagnosis of growth hormone deficiency. There are a number of tests that can be used to assess for growth hormone deficiency, and that includes the insulin tolerance test which is the gold standard. The issue here, though, of course, is that many sites cannot perform this because it requires an MD observation. I've done several hundred and patients may get ill as the hypoglycemia progresses. So it's something which, although it's a gold standard, not routinely done in all centers. The Argentine growth hormone releasing hormone test was used by many of us for many years. The problem is that growth hormone releasing hormone is not available, at least in the United States, and it's a test that we cannot utilize, at least in the United States. The glucagon test tends to be the one that is mostly utilized. It's fairly simple to perform. It requires intramuscular glucagon administration, and there's cutoff levels of 3.0 micrograms per liter, which for most patients, but as I'll show you, particularly with overweight patients, a lower cutoff is used. And mastomerelin, I'm gonna refer to in this presentation, is the oral growth hormone secretagogue. I'll be discussing a little bit about that as well. So the glucagon test, which again, tends to be the most utilized, really because of its ease of administration and monitoring. Patients can get nauseous from this, but that's usually managed well with Zofran or some other anti-emetic. The cutoff of 3.0 is what tends to be used. It's for all size and care levels for patients. A very good test for use. And there have been suggestions for using revised cutoffs of growth hormone levels for patients who are overweight. And I'm showing you here a study that really has been brought forward by the Mass General Group in Boston, looking at revised growth hormone cutoffs using a cutoff of one intagram per ml as cutoff. Otherwise, the potential for overdiagnosis of growth hormone deficiency in the higher BMI categories. Mastomerelin is the oral growth hormone secretagogue. It is used, indicated for the diagnosis of growth hormone deficiency. It is, because it's oral, it's a lot easier for many sites to use. In mastomerelin, the results correlate very high with insulin tolerance tests, and therefore, based on its reproducibility, it's considered an excellent test to use for growth hormone deficiency diagnosis. The cutoff has been used of 2.8 nanograms per ml, and this is what was approved by the Food and Drug Administration for cutoff standards for use for growth hormone deficiency testing. An issue, there are two issues to describe with use of mastomerelin. It's very well tolerated. Patients who have prolonged QTs, it's a bit problematic, because it can prolong the QT interval, so that needs to be assessed prior to using this test. It's also quite expensive, and a number of sites do not utilize the mastomerelin test because of its expense. And the last issue is that this mastomerelin was marketed by Novo Nordisk, but it's no longer being marketed by Novo Nordisk, and really, its future availability, at least in the United States, is a bit unclear at this point. So there may be some left in reserve for use now, but the future, we'll still have to find out about its availability. So if we look at the tests I described, and again, I'm trying to introduce these terms for you, and you'll be hearing more about these as we go with the next speakers, is that of the tests we have, the insulin tolerance test, which is considered the gold standard test for growth hormone provocation, is because of its accuracy, is difficult in terms of safety, in terms of risk of hypoglycemia, and potential risk for cardiovascular issues, if such were to happen. It's not very easy to perform, and MD has to be present. It's relatively inexpensive to use, but again, it's more challenging to use in the clinics. The glucagon test is accurate, it's safe, it's fairly simple to perform, it does not need an MD present, it's quite available, unlike the mastomerelin, which is the next one down, which again, its availability is a little bit unclear going forward, it's very accurate, and the other issue with mastomerelin is its cost, but otherwise, it's very easy to use, and for those of you who have tried it and utilized it, it does give accurate results. There are recommended cutoff points, I'm not gonna read all these for you, but essentially, for insulin tolerance tests, cutoffs are here. Glucagon, the cutoff is three, for patients who have BMIs less than 30, and more recently, as was showed in the guideline, in publications by ACE, an endocrine practice cutoff of one is recommended for patients who have BMI greater than 30, and mastomerelin, we discuss a cutoff of 2.8 is what has been used for cutoff for growth hormone deficiency. In conclusion, in diagnosing growth hormone deficiency, in the setting of deficiency of multiple pituitary axes, growth hormone stimulation tests may not be necessary. IGF-1 alone, particularly in the setting of otherwise normal pituitary function, is not sufficient for a diagnosis of growth hormone deficiency. Growth hormone stimulation tests often are needed for a diagnosis of growth hormone deficiency, and understanding the growth hormone stimulation tests in normal ranges really are important and critical for an accurate diagnosis. In children, other methods for diagnosis may be considered, and you'll be hearing about those in a few minutes. I wanna thank you, and I'm going to pass the podium to my colleague, Dr. Hoffman. Andy? Thank you, Larry. So, it's important for us to discuss what the clinical features of adult growth hormone deficiency are. Over the past 30 years, we've defined the syndrome as including problems with decreased bone mineral density, decreased strength and exercise capacity, increased abdominal and visceral fat, an abnormal cardiovascular lipid profile, decreased cardiovascular functioning, and a decrease in psychological well-being. Recent study looking at a large number of insurance records of patients with growth hormone deficiency has also shown that these individuals have a large number of comorbid conditions, and these include cardiovascular, hepatorenal, metabolic, and psychiatric. Prior to the availability of growth hormone, individuals with panhypopituitarism, even if they were treated with glucocorticoids, thyroid hormone, and sex steroids, had an increased mortality rate, as you can see from the studies in the bottom. However, once growth hormone became available, and most patients were treated with growth hormone, you can see that the standardized mortality rates are now approaching one, suggesting that growth hormone, first of all, is certainly not going to be detrimental to these patients, but might, in fact, provide an important health benefit. The major cause of growth hormone deficiency in our adult patients are pituitary tumors. In addition to that, craniopharyngiomas and other brain tumors, pituitary and whole-brain irradiation are also major contributors to this patient population. More recently, we've seen an increase in hypophysitis, either idiopathic, autoimmune hypophysitis, and now with the use of many checkpoint inhibitors, we're seeing hypopituitarism on the basis of those oncologic drugs. Rarely, sarcoidosis or tuberculosis can cause hypopituitarism and growth hormone deficiency. Traumatic brain injury and subarachnoid hemorrhage are also contributors. And then there's the population of individuals who had childhood onset growth hormone deficiency who remain growth hormone deficient throughout life, and those are mostly kids who had an organic cause or a genetic cause for their growth hormone deficiency. In comparison to the adult onset patients, the childhood onset individuals who are now adults tend to have more reduced bone mineral density and bone mass. They have more reduced muscle mass and they tend to have lower IGF-1 scores. On the other hand, they tend to have lower BMIs, less visceral fat, and higher HDL cholesterol. And generally, their quality of life scores tend to be the same. Now, there have been some consideration as to whether hypopituitarism leads to a shortened lifespan, as I showed you before. And there was a recent study looking at the actors who played the munchkins in The Wizard of Oz. And these were all growth hormone deficient individuals who, of course, never received growth hormone back in the 19-teens and 20s. And there has been data to suggest that there is decreased lifespan, at least in the female munchkin actors. Well, the goals of growth hormone replacement therapy really are to reverse all of the problems that I had mentioned before. We hope that they will have improved cognitive function and psychosocial well-being, that they'll have a reduced LDL cholesterol, an improved cardiovascular function, and exercise capacity. They should have decreased total and abdominal fat, slightly increased muscle mass and strength. And over the period of many years, they will also have modestly increased bone mineral density. In general, growth hormone is very well-tolerated in adults. When we first did the trials of giving adults with growth hormone, we started with very high levels, and then titrated the dose down because of side effects. We now do the reverse. We start with very low levels, we titrate up, and as a result, we rarely see much in the way of side effects. The most common ones we would see would be fetal edema, carpal tunnel syndrome, headache, and arthralgias. On occasion, we'll see worsening of glucose tolerance, but there's no evidence that growth hormone causes any de novo cancers. We'll start with the case study. This is a 24-year-old woman who presented with severe headaches, secondary amenorrhea, fatigue, a 25-pound weight gain, lethargy, all of these developing over the past year and a half, and she's been unable to work for the past six months. Her laboratory studies show low gonadotropins and a low estradiol of 20. Her prolactin is normal. Her free T4 is 0.7, with a normal of 0.6 to 1.6, and the TSH is normal at one. An AM cortisol was 7.1 and an ACTH was 22, and the IGF-1 was 51, with a normal range being 180 to 360 for a woman her age. The MRI of her pituitary showed a one and a half centimeter non-invasive pituitary adenoma that was not close to the optic chiasm. She was diagnosed with a non-secretory pituitary adenoma, secondary hypogonadism, and growth hormone deficiency by her endocrinologist, and no growth hormone stimulation test was performed. She declined surgical excision of the tumor and elected to have watchful waiting with frequent MRIs and biochemical monitoring. Birth control pills containing estrogen and progesterone prescribed for sex steroid replacement therapy, and she was also started on growth hormone, daily growth hormone, at 0.6 milligrams per day. Okay, so here's your question. She is at risk for developing which of the following? Vasopressin deficiency, hyperprolactinemia, hyperthyroidism, ovarian cysts, or secondary adrenal insufficiency. Once you start growth hormone therapy, you have to recognize that there are many hormone-hormone interactions that are gonna be very important for you to check for your patient. Growth hormone, for example, will stimulate the degradation of thyroid hormone to T3, and therefore the free T4 levels may fall, necessitating an increase in thyroid hormone replacement. Or you might actually unmask secondary hypothyroidism. Similarly, growth hormone stimulates the metabolism of cortisol, the active hormone, to the inactive metabolite, cortisone. And so when you start growth hormone therapy, you might unmask secondary adrenal insufficiency. Giving thyroid hormone to somebody in this situation without giving the hydrocortisone may also cause an adrenal crisis. Growth hormone will not be able to stimulate IGF-1 as well in women as in men, and this is especially true in women who are taking oral estrogens, because estrogen inhibits the ability of growth hormone to increase the hepatic production of IGF-1. Androgens will give you a modest increase in IGF-1 levels in addition to growth hormone. Okay, this is a sort of a truism from our former Surgeon General. If you don't take the medicines, they're just not going to work. And I'm happy to announce that the future is here, because we've been talking for a long time as to whether a long-acting growth hormone preparation might enhance adherence to the daily growth hormone therapy. So this is our hope. However, we have to understand that there are questions. Will intermittent growth hormone secretion be needed for robust growth hormone action? Would a long-acting growth hormone increase IGF-1, or would there be tachyphylaxis or downregulation of growth hormone receptors? Would constant levels of growth hormone that would be seen in a long-acting product lead to acromegaly or a whole new set of induced proteins and potential side effects? And really, wouldn't compliance improve with a weekly or longer even injection schedule? These are all important questions that need to be answered. As you know, growth hormone is secreted in a pulsatile manner. Much of the day, the growth hormone levels are extremely low, even undetectable in most assays. So you simply can't measure an isolated growth hormone to see whether somebody is growth hormone deficient, as Dr. Katznelson described. If we look at growth hormone pulsatility in a normal person, if you look on the right, you can see that there are multiple pulses throughout the day, often more at night. The levels tend to be higher in women than in men. On the left are three patients with acromegaly. They have the same mean growth hormone levels as the controls on the right. But as you can see, it essentially is a pulsatile. The growth hormone levels are essentially the same throughout the day. And even though their mean growth hormone levels are matched and are the same, the IGF-1 levels are very high, suggesting that if you have this constant secretion of growth hormone, you might end up with high IGF-1 and acromegaly. So this would be a concern with a long-acting product. The importance of pulsatility was taught to us many, many years ago because of GnRH. And we knew that GnRH pulses will stimulate LH and FSH secretion, but that a constant infusion of LH or GnRH will lead to a chemical castration and an inhibition of gonadotropin secretion. So we use these analogs now as chemical castrates. Similarly, with parathyroid hormone, the constant endogenous secretion of PTH can lead to decreased bone density, but we now give daily pulsatile injections of PTH to increase bone density. So the chronobiology of these hormones can make a difference. And the question is, does it make a difference with the growth hormone IGF system? And this shows what the IGF, I'm sorry, the growth hormone levels are when a pegylated long-acting growth hormone is given. The levels are fairly constant over the week. Well, a couple of studies were done many years ago to suggest that, in fact, this tachyphylaxis does not occur. In the first study, growth hormone and IGF-1 were measured in 13 patients who were given four weeks of either once daily or continuous IGF, continuous growth hormone given by a portable pump. And as you can see, the IGF-1 levels remain the same in those individuals. And when this was continued for six months in a separate set of subjects, the IGF-1 levels remained elevated, indicating that this constant level of growth hormone does not lead to tachyphylaxis or to acromegalyc changes over at least a period of six months. So what would be the attributes of an ideal long-acting product? Hopefully, the mode of delivery would use a small bore needle. You'd only need to give one injection. And you could give it infrequently, perhaps once a week. The efficacy should be non-inferior to daily growth hormone. And the safety profile should also be the same. One would hope that it would not include the induction of antibodies causing acromegalyc signs or symptoms or any novel effects because of the analog's novel properties. And finally, the most important, I think, for clinical practice is that the cost has to be somewhat comparable, that if this is going to be very expensive, insurance simply will not pay for it. So this is a study that was done recently and published in the JCEM, where it's a Phase III randomized trial of weekly growth hormone and somatopacitin. And as you can see, compared to placebo, somatopacitin was an effective growth hormone agent, leading to decreases in truncal and visceral fat and increases in lean body mass. And it was non-inferior to the daily growth hormone. So this is an example where we have a long-acting product that is non-inferior to the product that we're currently using. You must understand that most studies now have been very short-term. We don't have data that extends for years and years. Now, over the past 20-plus years, there have been numerous long-acting growth hormone products. Back in the 1990s, there was a product that was made by Genentech that was a depot form of growth hormone, and it was actually marketed for children. It required multiple injections that left a big lump on the skin, and it really didn't work quite as well as daily growth hormone. It also worked for adult growth hormone, but it was never growth hormone deficiency, but it was never marketed for that, and the drug was taken off the market. There was another long-acting preparation due to a depot form that was done by the LG Corporation that was actually approved but never marketed in Europe. It was used to some extent for pediatric growth hormone deficiency in Korea, but again, it's a product that I think has no future. We have several products, however, that are currently used. So, pegylation is one way to increase the half-life of a peptide. You can attach a large polyethylene glycol to a molecule, and the growth hormone will circulate for a long period of time. Multiple pegylated growth hormone products were tried, and many of them had very bad side effects and were dropped. Nonetheless, there is a pegylated product that's marketed in China by GenScience, and it is marketed for pediatric growth hormone deficiency, and they've had Phase III trials for adult growth hormone deficiency, but as far as I know, it is only being used in China. There is another product, Lonapeg somatropin, that is a native growth hormone that is attached by a linker protein to a large polyethylene glycol molecule. The peg itself does not enter the cell, and this product has been approved for pediatric growth hormone deficiency. It's being marketed by Ascendus, and Phase III trials are in progress for adult growth hormone deficiency, but it is available in the U.S. for pediatric growth hormone deficiency. Somapacetin is a growth hormone molecule that has now been approved and marketed for adult growth hormone and pediatric growth hormone deficiency. It is a growth hormone analog with one amino acid change, and it is attached with a linker that will bind to serum albumin, and it is the study that I showed you just a moment ago. Somatrogen has been approved for pediatric growth hormone deficiency in Europe, and it is a growth hormone molecule. It's a fusion molecule that has three copies of the C-terminal peptide of human chorionic anatotropin attached that extends the half-life of growth hormone. It is approved in Europe and Japan. It is for the FDA in the United States all for pediatric and not adult growth hormone deficiency. And there are a number of other growth hormone fusion proteins that have been in preclinical trials, but nothing else that I know of is on the horizon. This is another example from the Somapacetin study looking at pharmacokinetics, which showed the levels of growth hormone and IGF-1 levels, and you can see that the levels do remain in a physiologic state over a period of one week, so the drug can be given once a week. The questions that then come up is to when do you measure the IGF-1, and these are going to do that somewhere in the middle of the week, but it means that you have to time your dosing much more carefully than you do with daily growth hormone. Now, there are safety considerations, because occasionally you do have superphysiologic elevations of growth hormone. I mean, growth hormone normally is essentially undetectable during the day, and now with these long-acting preparations, the growth hormone is going to be measurable throughout the day. The trough growth hormone concentrations, therefore, are going to be above physiologic levels. There may be a non-physiologic tissue distribution due to the distinct biological features of these products, and the specific chemical composition of each long-acting growth hormone product may confer unique safety issues. And one of the things I'd like to show is this is an example of hormone action of HCG and LH. Now, HCG and LH both interact at the same receptor, the LH-CGR receptor. The difference between the two is that HCG has this C-terminal tail that adds 28 amino acids, so it's essentially a long-acting LH analog. And if you look at its action in some cell cultures, you can see that LH primarily stimulates G sub Q and phospholipase C, whereas HCG, which is interacting with the same receptor, primarily stimulates G sub S and adenylate cyclase. And therefore, there may be some differences with these longer-acting analogs as to other actions that may be detrimental or may be beneficial. So for the future, we need to develop methods that will assess adherence so that we can tell whether patients actually are taking their medicine in a more compliant fashion over time. More importantly, however, I think we need to have long surveillance registries, essential for understanding the impact of the chronic exposure to all preparations of long-acting and even short-acting growth hormone. And we were hoping that this should be mandated by regulatory agencies because this would need to include the assessment of long-term efficacy, risk effectiveness, disease burden, quality of life, and safety measures. Well, the regulatory agencies haven't stepped up, but an organization called Globreg has. This is an organization out of the University of Glasgow. Globreg supports the development of specific studies with a focus on the effectiveness of long-term safety and a routine collection of real-world data on specific classes of drugs. And they are going to be looking at a variety of drugs. This is phase four studies, if you will, real-world data. And it will act as a longitudinal registry for the effectiveness and long-term safety of these drugs where registry studies are not being done. Therefore, it would be an ideal group for us to work with. There is a growth hormone scientific study group as part of Globreg. And currently, they have developed a very good working relationship with pediatrics. And they've come up with forms that can be filled out for your patients with regular follow-ups so that the registry will be complete. And I know that some of the pharmaceutical companies developing the long-acting products are going to be helping with this registry. And I think it will be very, very important. We're planning to work with them to set up an adult growth hormone deficiency registry as well. So in conclusion, there are numerous novel long-acting growth hormone formulations in development and now in clinical practice for the treatment of children and adults. And it may be that there will be more that will be tested in the near future. In these relatively short-term studies, some of the long-acting preparations are not inferior to daily growth hormone in their ability to increase IGF-1 and improve growth and body composition. The optimal times for assessing efficacy will depend on each product. And we'll have to look at long-term effects of these medications. Thank you. Thank you, Dr. Hoffman. I now invite Dr. Duvall to come to speak about the approach to a pediatric population with growth hormone deficiency. Thank you for inviting me to speak today. I was charged with summarizing pediatric growth hormone deficiency and long-acting hormones as a perspective for you may have a perspective when someone is in your office to say they were on growth hormone as a child and how I approach diagnosis and treatment and then put long-acting growth hormone in context. So my talk will be framed by a patient of mine. I saw a six-year-old female referred for growth attenuation. As you can see by her growth chart there, we have growth charts in pediatrics, and her growth rate is three and a half centimeters per year, which I can tell you is less than fifth percentile for age. And as you can tell by the growth chart, she is crossing percentiles very dramatically there. Her past birth and medical history were remarkable, as you can read. Her birth rate was normal. And her mid-parental height is at the 25th percentile. She did not have constitutional delay in her family history. And again, her physical exam was unmarkable, and she did not have any features of Turner's syndrome, which is on the diagnostic differential for us. So as peds endos, if we encountered a child with growth attenuation, our differential diagnosis is quite long and includes not only endocrinopathies that directly or indirectly affect growth hormone secretions, but non-endocrinopathies like malnutrition or GI disease or other chronic diseases that indirectly affect growth hormone secretion, and that's that third row there. And the last other causes are skeletal diseases and chromosomal disorders and other syndromic disorders. So when we are confronted with a child with growth attenuation, we have to go through these growth differential diagnoses. And I have presented the lab evaluation there in the second column. And also in pediatrics, since the growth plates are not fused, we use bone ages. And anything that affects growth hormone secretion, whether directly or indirectly, is going to result in bone maturation that is younger than the patient's chronological age. Anything with a skeletal component contributing to their growth attenuation is going to have a bone maturation the same age as their growth hormone secretion, whether directly or indirectly, is not affected. So back to my six-year-old. Her laboratory evaluation was unremarkable. I wanted to point out that her thyroid testing was normal, no evidence of secondary hypothyroidism, and prolactin was normal, and a screen for celiac was negative, and her IGF-1 is low for age. So IGF-1 changes with age and puberty, so we have norms for each age, and that's the norm for her particular age and sex. And she had no events of Turner syndrome, and her bone age was delayed. So in children, testing for growth hormone deficiency is based not only on your oxylogical criteria, but we also do growth hormone stimulation testing like y'all do in adults, except we use two agents instead of one, and a subsequent slide to this will explain why. But when I have a child with growth attenuation and IGF-1 levels, this is how I think about who to perform a growth hormone stimulation test in and who not to. Like in adults, if they have more than two or three pituitary hormones affected, with low IGF-1, you can assume growth hormone deficiency, and we don't have to do any provocative testing. In practice, at initial presentation, if I have a child with growth attenuation with pituitary hormone defects, including low IGF-1, I am sending them straight to the MRI to look for that craniofungioma, and I'm not doing stimulation testing. So on the second row there is the unique situation of a child who's had intracranial irradiation. So just like in adults, children with intracranial irradiation develop growth hormone deficiency as the first pituitary hormone deficiency after irradiation. And it was a recent recommendation by, let's see, Sayre et al, in a recent JCM article, that only one agent for provocative testing is needed in children who have a history of cranial irradiation, and growth attenuation is needed for growth hormone provocative testing to prove growth hormone deficiency. Now, I also wanna point out that in people, in children with cranial irradiation, the IGF-1 level is, sensitivity and specificity goes down to 30%. It is about 80% in other populations, but again, in the intracranial, with history of irradiation, it's a lower sensitivity and specificity, so you cannot rely on that like your other populations. And the last is the most often seen in clinical practice, where if you have a child with no other pituitary deficiency and meets oxylogical criteria, in school-aged children, it's a growth velocity usually about less than four centimeters per year, and you know that constitutional delay in growth and puberty is unlikely based on family history, and you have a low IGF-1, and this is whom I choose to do growth hormone provocative testing with two agents in, we do in pediatrics. So this case, sorry, this study done in the 1990s proves why we use two provocative tests in pediatrics. It's because the reliability of provocative tests, one agent is not very good in normally growing children. So in this study of nearly 500 normally growing children, aged between four and 17 years, with healthy normal BMI in various stages of puberty, and proving that they had normal IGF-1 and normal bone age, this graph shows that their mean growth hormone level, and growth hormone level cutoff of 10 was historically established in the 1960s and 70s to discern growth hormone sufficiency from insufficiency in children. As you can see, of the agents used, PE is physical activity, or physical exercise, yes, that is a provocateur of growth hormone release in children. The insulin tolerance test is ITT, arginine, clonidine, and L-double-mean are the agents we use. We also use glucagon as well. As you can see, the mean peak growth hormone in normally growing children is above that historical cutoff of 10, so whether 12, 13, 16, 13, or around 13, but you can see the 2 1⁄2 to 97th percentile I have there above the graph is that many normally growing children are below that historical cutoff of 10 using one of these provocative tests. So for that reason, number one, we use two provocative tests, and number two, given this data, I choose very carefully whom I select for growth hormone simulation testing. So once we've decided to do the provocative test with our two agents, how do we interpret these tests? So there's lots of variability in how people interpret the results of these tests. So the growth hormone guidelines from 2016 for childhood diagnosis and treatment of growth hormone deficiency is quoted here. Very low peak growth hormone levels on testing are consistent with severe growth hormone deficiency, and patients with such results are expected to benefit from growth hormone treatment. The threshold test result that distinguishes normal from partial growth hormone deficiency that response treatment has not been well established. So what do I do in that vague statement? How do I interpret my results in clinic? And I show you the algorithm there, so how I interpret it, and each pediatric endocrinologist is gonna interpret this a little bit differently, but this is how I do it. And I think most people in the field if you have a peak, all your peak growth hormone, all your growth hormone levels are less than five, then you have classic growth hormone deficiency, and these children respond well to growth hormone, and you feel confident in the diagnosis. If any one peak is greater than 10, then the child does not have growth hormone deficiency. However, if your peak growth hormone with these two agents is somewhere in between, whether between that magic number of five and the new cutoff that for the sensitive growth hormone that your lab is using, whether that's deficient or not, I call it probable growth hormone deficiency, and whether your peak growth hormone that you achieved with this two agent is between the cutoff for your sensitive lab and that historic of 10, whether that's possible, whether that's a normal child or possible partial growth hormone deficiency, that's where you're gonna have a lot of variability from peds endo to peds endo. So I use arginine, the two agents I use is arginine and dopamine. Arginine and clonidine are also very popular agents to pair together. And of course I picked a case where all the, there is no peak growth hormone greater than five, so this was not a difficult case to diagnose. And with that, I did do the MRI, and this young girl had no pituitary defects, no ectopic posterior pituitary. The radiologist did report there's a slight small pituitary for age. I did put a question mark there because there is no norms for pituitary size per age, and that is a subjective assignment from the radiologist, so I don't know if that's, how to interpret that. So when you have testing that can give you such results that can be difficult to interpret or people interpret very differently, it will introduce bias into our diagnoses. So I wanted to point out to you the bias and diagnoses of growth hormone deficiency in children. So on the graph on the left is the gender distribution with percent males and the y-axis of various diagnoses that we use growth hormone in children, both in the United States, Europe, Australia, and Asia. I want to point out that the purple, idiopathic growth hormone deficiency on the far right of each group is the isolated idiopathic growth hormone deficiency. As you can see, in all areas of the world, there is a greater than 70% of people diagnosed are boys, and in Europe, they're a little less biased than in Asia or in the US. And I also want to point out that congenital and organic growth hormone deficiency, and that's the first dark blue and the red line there for each region group, that is also slightly a male predominance there in each country as well. But I would like you to know that the idiopathic growth hormone deficiency is much more diagnosed in males than in females. And this is based on a national or international registry, KIGS, sponsored by a pharmaceutical company. And the graph on the right, or the table on the right, is specific to the US data. And this is also US data for KIGS, same registry, but this is looking at racial data. So this was presented in a little bit different way. The first boxed, red boxed column is the expected frequency of treatment with growth hormone based on the frequency of having short stature defined as minus 2.25 SD. From your race, so as you can see, the white is about 63%, and black you'd expect 9%, and Hispanic 12%. However, the other, an idiopathic growth hormone deficiency, again, it's a white predominance, 84%, when 63% would be expected. And even acquired growth hormone deficiency is 83% when 63% is expected. And interestingly, point out that idiopathic growth hormone deficiency is 3% black, but the congenital is 11%. So in the black population, we are picking up and diagnosed congenital, but not idiopathic. And especially noted for Hispanic as well. So again, we seem to be diagnosing idiopathic growth hormone deficiency more often in white populations. So a summary for diagnosis. The differential diagnosis of attenuated growth is very broad, includes hormonal and non-hormonal causes. It's difficult to distinguish between constitutional delay of growth in puberty and isolated partial, probable or possible, whatever term you wanna use, growth hormone deficiency. And growth hormone cutoffs, diagnosed deficiency using the provocative tests are open to interpretation. And there's section racial differences in diagnosis and treatment of growth hormone in the US. So on to, yes, on to treatment. So my six-year-old girl has idiopathic isolated growth hormone deficiency. And I knew her from many years ago, so my treatment option was daily growth hormone. So since we've had recombinant growth hormone since 1985 and using it for growth hormone deficiency in children since 1985, we have decades of data on efficacy and safety. So with treatment, we know that achieved adult height standard deviation score minus mid-parental standard deviation score, and you're always comparing to genetic family potential, is minus eight to minus four standard deviation. So what that means is that children approach their mid-parental height potential, but they don't exceed it. And again, and those that do achieve higher adult height tend to have a higher genetic potential, a higher mid-parental height. They also have the greatest response in that first year of therapy. They are on growth hormone for a longer time. And as you can imagine, they have a more severe growth hormone deficiency as revealed on their provocative testing. So what products are available for children in the US? So the first seven are the classic daily growth hormone with their names and the frequency of administration and which regions they are available. So they are widely available, the daily. And the last three are the weekly and long-acting growth hormone formulations, as mentioned by Dr. Huffman and Katznelson. Skytropha and Somapacitan are approved in the US, at least for children. So Matradon is not yet approved in the US for children, it is approved in Europe, but I know that the company is actively working with the FDA to get it approved in the US. So Pharmaconex is a little bit different in children than adults. Children are not little adults. So these studies were done using growth-finding studies. I want you for Lonapeg somatotropin in the upper left, Somatopacitan in the upper right, and Somatrogon in the lower. Please know that there's multiple dosing because they were dose-finding studies when they did these pharmacokinetics. Please know that for the Lonapeg somatotropin, that the final FDA-approved dose is actually between the blue and, sorry, the green and the red lines. But as you can see, though, there's a peak at day four after administration and a trough at day seven. And please know that all of these studies were on week 12 of treatment, so that's why there's an 83 on the x-axis on that first graph. And as you can see for the Somatopacitan, there's a similar pattern for these pharmacokinetics on day, peak on day one to two with a trough on day seven. And please know it is the dark blue line that is the FDA-approved dose now. Also on the Somatopacitan graph, they have the nice sinusoidal wave is daily growth hormone pharmacokinetics effect on IGF-1. And the Somatrogon, again, the approved dose in Europe is the green line, so the top one, and again, same pattern, a peak on day about two with a trough on day seven. So again, most of the formulations have, despite their different mechanisms of action, are still have that peak on day one or two, sometimes day three, with a trough on day seven. So this is Lonapeg somatotropin, and this was the randomized control trial that got this FDA-approved for use in the U.S. So their outcome was height change SDS from baseline. So the first half of this graph is the height study. That's the 12-month study. Sorry, 52-week study. And then the last part, the enlightened, was the extension for another year. So in the first 12 months, they were compared to daily growth hormone. And then in the second 12 months, everybody got switched to weekly growth hormone. So like in adults, the outcomes were non-inferiority to growth hormone, to daily growth hormone, excuse me. And as you can see, compared to baseline is there on the far left, compared to baseline at week 52, there is both long-acting long-dependent somatotropin and daily growth hormone improved their height SDS, got more towards zero. And the improvement endured in year two when everybody was switched to the weekly growth hormone. So there is not a falling off of effect. The effect in the efficacy is there in year two as well. The compared trial of somapacetam to daily growth hormone was the phase three real for trial. In this multinational study, 200 children were enrolled, randomized two to one somapacetam to daily growth hormone. Somapacetam at 0.16 milligrams per kilogram per week was the dose chosen as it demonstrated the highest efficacy in phase two trials. This dose was compared to daily growth hormone at a dose of 34 micrograms per kilogram per day. The primary endpoint was analyzed growth velocity. As you can see here at baseline prior to treatment, the analyzed growth velocity was similar between groups of four centimeters per year. After 52 weeks of therapy, there was a similar rise in growth velocity to around 11 centimeters per year in the daily growth hormone and somapacetam groups. The treatment difference of one half of a centimeter was not statistically significant. Therefore, weekly somapacetam had similar growth velocity outcomes after 52 weeks to daily growth hormone, thus demonstrating non-inferiority. There was no significant safety events during the trial. Okay, so this is the Soma, that's the third one, Soma Trogon, thank you. Okay, so many Somas. Okay, so this is the data for Soma Trogon. This study actually had the most number of children in it. If you notice, there was about 224 children in it. The data from Lonapeg somatotropin and somatopacetam, it were about 50 to 100 children each. So this actually, this study had the higher number of children at 224. And the height velocity data compared to daily growth hormone is there on the left graph with the height SDSC score there on the right graph. As you can see, the change in height velocity compared to daily somatotropin there in orange is similar between weekly and daily. And the height SDS from baseline, the change is similar to daily growth hormone. If you notice, the change in height SDS from baseline is not as dramatic as the other two studies, which I think is because of their higher numbers of patients enrolled and the higher heterogeneity of the population. You're gonna have some children who just are not, don't respond as robustly to either daily or weekly growth hormone. Okay, switching to adverse events. So for daily growth hormone, because of the registries performed by the various growth hormone manufacturing companies starting in the early 90s and up to the mid 2000s, we have almost a million patient year data from these different registries, the NCGIS, KIGS, and Genesis studies that give us very accurate adverse effects. So we know very accurately that the incidence of intracranial hypertension in children with starting growth hormone is one per 1,000, and SCFI is 73 per 1,000, and we know that there may be scoliosis progression, and diabetes, not diabetes progression, and the data on the long-term risk of cancer is still controversial. But I wanna point out that we have less than 1,500 patient years for data on adverse effect for weekly growth hormones, so we just don't have this data yet, and this plays into the importance mentioned by Dr. Huffman about the global net to registries to get this data so we can accurately counsel our patients. This is a quick graph comparing the Lonapeg somatotropin, somatopacitan, and somatrogon, what their dosing improved in kids, how it's supplied. The Lonapeg somatotropin is a fixed-dose injector, unlike the other forms, and when to check IGF-1 for dose monitoring, and most of them say day four represents your average IGF-1 during the week, and Lonapeg somatotropin actually has a published calculator to use after achieving steady state after the fifth dose, so you don't have to do an IGF-1 on day four. Okay, with that, I have, this is my patient who I started on daily growth hormone because this was years ago, and you can see the nice growth response, and she's still growing. And we'll next have a review and discussion about the patient's best to choose for long-acting therapy. Thank you. Thank you, Dr. Vo. How comfortable are you in using long-acting growth hormone products in your practice? What is the likelihood of a long-acting growth hormone products improving a patient's compliance with therapy? And you see the answers. Okay, how concerned are you about the safety issues utilizing the long-acting products? Can I ask both Drs. Duvall and Dr. Hoffman what your thoughts are? Well, I think any time a new product comes out, that a physician should be wary and concerned about potential side effects that may not have popped up during the phase three trials. The question is the concern over a serious side effect or a minor one, and my own feeling on this is that I think I would be concerned but would still prescribe the drug because I think the safety data looks good and because we're going to be monitoring it very carefully. But I think it makes sense to feel some concern over any new drug. So? Go ahead. In regards to long-term safety in children, you can probably imagine I do have some concerns because we don't have that long, many years data like you do from daily growth hormone. But yet, that data will come because we are in the same place, we are the same place we are in 1990 with daily growth hormone, we didn't know the long-term side effects, and luckily it was very safe. So my only thoughts was that as more children get treated, we're gonna have that data so we can give that to parents about the frequency of these side effects. But if I feel a child would very much benefit from growth hormone and I can't get them to do the daily shot, I'm gonna do the weekly just to try to improve that compliance. Thank you. Now, I'm gonna use the next few minutes to pose some questions to the speakers here that I thought would be reasonable for this audience to hear and think about. The first question, and I'm gonna start with Dr. Duvall on this, you have much more experience in pediatric room, of course, than we do in adults using long-acting growth hormone preparations. Who would be the most appropriate patient for long-acting growth hormone medication in a perfect payer world? Oh, thank you. Well, believe it or not, although I didn't have time to mention the transition patient, I think that the transition adolescent who is done with daily growth hormone for heights yet has multiple tertiary hormone deficiencies and needs that daily, needs to continue that daily growth hormone but is done with injections and I cannot convince them to do it because the benefits are so not tangible to them. I think that that would be a great person to try to for the weekly growth hormone. In regards to the pediatric growing population, we often have two parent, or sorry, split households and getting the growth hormone back from one household to the other can be tricky and there's lots of missed doses. And again, the surly adolescence is also a great population for this to use it in. And then one of the formulations doesn't need refrigeration unlike daily growth hormone. So in very active families, that may be an attractive option. Thank you. Dr. Hoffman, you try. You know, the vast majority, up to 80 or 90% of adults with growth hormone deficiency are not getting growth hormone. And I know that in my practice, the major reason for a patient rejecting growth hormone is the idea of having to take a daily shot. And I do think that those individuals would be perfect people to offer a long-acting product. And when I've mentioned it to them in a theoretical way, most of them say they would be very willing to try a weekly product but they didn't wanna do the daily shot. Thank you. And I think a perfect pair world is always kind of a tough hypothetical scenario to use given we know the challenge, at least I'm familiar with, in the adult realm of having insurance coverage for the growth hormone therapy. And I'm gonna pose this question to Dr. Duvall. You gave some really tantalizing, really important information on potential bias in the diagnosis of growth hormone deficiency in children. And I'm kind of curious as to what are some of the biases you have seen in the diagnosis or the referral process in your patient population? So, in general, it's been studied that there are biases in the parent expressing concern to the general provider, general pediatrician. There's biases in the referral to an endocrinologist. There's biases in the endocrinology and who they choose to do stimulation tests. So there's gender bias at all points in the referral process, which contributes to that general gender bias. And there's also some work being done at a qualitative, some qualitative studies going on, looking at different populations and what their attitudes are about assure stature and some populations are just not as concerned as other populations and it's quite, and so they won't bring it up to their general practitioner. So it's biases at all stages. Thank you. For either of you, Dr. Hoffman, Dr. Duvall, can an IGF-1 level be used solely for the diagnosis of growth hormone deficiency? For example, if there's more than three or four standard deviations below the mean, as an example? The IGF-1 can only be used in adult medicine by itself if you have somebody who's panhyperturatory. They have three other systems out. There are other things beside growth hormone that will lower the IGF-1, including nutrition, some drugs, so that just in a low IGF-1 by itself is not diagnostic. And it's also important to recognize that up to a third of patients with bona fide growth hormone deficiency will have an IGF-1 level within the normal range. Dr. Duvall? In regards to, in children, you have to have both oxylogical criteria, so diminished growth rates. Just because in children, other factors like malnutrition and other disease can lower your IGF-1. We, I do oxylogical criteria and IGF-1, and I don't do the stimulation test, only if there are other pituitary hormones affected. Thank you. There are a couple questions on patient populations, maybe or maybe not to be concerned about. For Dr. Duvall, there were a couple questions on if a child with scoliosis or some kind of other bony deformity, would that be, how would you approach that with your patient in terms of growth hormone replacement therapy? So growth hormone can worsen scoliosis, not because of the growth hormone itself, because any sort of growth in a child is going to worsen the scoliosis. So again, lots of discussion with the family. I still do growth hormone. Possibly I'll not try to induce such a great growth velocity, although those in PEDS-UNDO know that those with severe, children with severe growth hormone deficiency need very little growth hormone to take off. So again, it's a lot of discussion and evidence of the pros, cons, and get your orthopedic surgeon on board if you need to. There's another question. I'm gonna change the question. For Dr. Duvall, on the question of if you have a patient on short-acting growth hormone and now you're thinking of switching to long-acting growth hormone, methodologically, procedurally, how do you do that? So I've talked to the companies about this, just to make sure I'm doing it right. So you don't have to have a washout period or anything. You can go from straight, their daily growth hormone to the next day, do it weekly. For the Lonapeg somatotropin, it does take five doses or five weeks for you to get to a steady state for an IGF-1 to be helpful. So you do have to wait until after the fifth dose. Yeah, and as far as dose conversion, there is no information about dose conversion. The prescribed, the approved dose for Lonapeg somatotropin, for which I have the most experience with because it's out longer than a month. And the dose is an average dose amongst all my patients with growth hormone deficiency. So I think if I had a child with severe growth hormone deficiency who is very sensitive and grew very well on very low doses of growth hormone, I would not use the FDA-approved dose for Lonapeg somatotropin. I would use a lower dose. I would use a lower dose on those very responsive children. Thank you. And I wanna thank the speakers very much. Thank you very much. Thank you.

novel long-acting therapies

growth hormone deficiency

diagnosis

treatment plans

insulin tolerance test

glucagon test

mastomerelin

Argentine growth hormone releasing hormone test

pediatric population

growth hormone stimulation testing

long-acting growth hormone products