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Thank you very much for the invitation. Um I'm happy to talk about uh growth hormone therapy for Children with growth hormone deficiency. Um These are my disclosures. I am a consultant for a number of companies developing therapies for Children and have been in a clinical investigator on a number of clinical trials. I will not be discussing any off label indications. These are my learning objectives. Um We want to learn to implement individualized I GF one monitoring strategies to optimize therapy for patients receiving daily or long acting growth hormone. We want to interpret the fluctuations and I GF one levels to make data driven decisions on dosing and therapy adjustments. Tailor the monitoring approaches based upon the pharmacokinetic and pharmacodynamic differences between daily growth hormone and long acting growth hormone therapies and apply long term surveillance data to ensure patient safety efficacy and adherence during treatment. I'll start by talking about daily growth hormone which uh we are all familiar with uh since it was approved in 1985 for the treatment of uh pediatric growth hormone deficiency in 1996 for adult growth hormone deficiency, there are multiple different brands of uh biosynthetic growth hormone products that are currently FDA licensed for daily use in both pediatric and adult growth hormone deficiency. The safety profile is uh well known with over 600,000 patient years of safety data from clinical registries, injection site reactions, headache, muscle or joint aches and fluid retention can be some of the common side effects in adults. We see carpal tunnel syndrome, edema, arthralgias and elevated blood sugar with an increased risk of type two diabetes. And then rarely, we see intracranial hypertension and subcapital epiphysis as rare concerning side effects from an uh contraindication perspective. We want to think about uh not prescribing growth hormone um in the setting of active malignancy, acute critical illness, severe obesity in the setting of uh Prader Willi Syndrome. Um closed epiphyses in Children, diabetic retinopathy or hypersensitivity. From an efficacy perspective, we have seen significant improvement in linear growth with growth hormone therapy for Children with pediatric growth hormone deficiency. And we may see near normal adult height in those Children in adults, it improves body composition, increases lean mass and bone density decreases fat mass, improves exercise capacity and quality of life and normalizes IGF one therapy. But the long term impact on cardiovascular mortality is still under study. So, I'd like to present a case of a patient of mine who is a 12 year, six month old female with growth hormone deficiency diagnosed when she was two due to an ectopic posterior pituitary gland and stalk interruption at the time. Um She is seen she's 10 or five and she's on transdermal estradiol. She's on daily growth hormone 0.3 mg per kilogram per week and she reports that she's missing about one dose per week on daily. Her I GF one is 314 nanograms per deciliter with a range of 178 to 636 or negative 0.4 sds. So we'll talk about her case as uh we come later into uh interpreting I GF one values. So the FDA approved uses of daily growth hormone uh include growth hormone deficiency as well as a number of other non growth hormone um deficient uh indications. Today, I will be focusing solely on growth hormone deficiency. These are the near adult height in pediatric growth hormone deficiency. And what I'd like to show is that on in each panel, we have uh registry data uh with the dark blue line on the left being um starting or baseline initial height as they enter into the registry and they're near near adult height um after time on therapy. So in each of the registries that we see here for different uh daily growth hormone products, we see a significant improvement in adult height um but that we have not actually achieved the mean. And so I think it's important to recognize that with daily, we've had a significant improvement in height outcomes, but we haven't achieved the goal of uh zero sds or mean adult height at the normal range. So it's a question as to whether that's because um patients aren't taking the medication or if we aren't giving the best dose or if they don't continue the treatment long enough. And lastly, if we missed a uh an important critical window of early therapy that was we were unable to overcome. So, non adherence with daily growth, hormone therapy is common and it's associated with significantly reduced linear growth. Three studies shown here, one in the US, one in New Zealand and one in Spain show that there's a variability in the degree of noncompliance and the impact that it has on growth. So in the US study, 10% missed more than 15 injections per month. The high velocity was two thirds of that achieved by patients missing fewer injections. In the classic New Zealand study, over two thirds missed one injection per week. And again, there was a reduction in height velocity standard deviation score in those who were missing uh growth hormone doses. And in the Spanish study, moderate to poor adherence was seen in as many as a third of the patients with a lower height SDS and lower I GF one SDS seen in those uh patients. So non adherence tends to increase with time on therapy and is more common in adolescents and it may be as high as 70% in some of our patient populations. So it's a significant challenge to um ensure that we're getting the best outcomes when we're not taking. Uh our patients are taking the medication. So it's important to recognize that we've had daily growth hormone therapy for a long time and we have good evidence of efficacy and safety. We've got a correlation between the efficacy and improved quality of life. But therapy with daily growth hormone injections is a burden to the patient and caregivers and is associated with non adherence that may lead to lower height outcomes. Patient and family dis dissatisfaction and also long term health changes in bone health, body composition and cardiovascular health because of inadequate adherence. So looking into the future of growth hormone therapies, long acting growth hormone is expected to improve adherence in patients on therapy, thereby increasing the potential for better outcomes. There have been many attempts to make uh to create a long acting growth hormone pre uh preparation using a variety of technologies such as depo pegylation, noncovalent albumin binding and fusion proteins. And I'll talk about some of these as the talk goes on. The ideal characteristics of a long acting growth hormone is that it would provide all the benefits of naturally secreted growth hormone. The free growth hormone molecule would reach all of the target tissues. We could administer it with a small uh needle in a small volume. It would be easy to administer with a user-friendly device. It would be room temperature stable and painfree or similarly tolerable to daily growth hormone therapy. And it would be a lack of immunogenicity comparable to daily growth hormone. So, how do we make the injection of growth hormone last longer? We can do it by delaying the absorption from the subcutaneous space through incorporation into microspheres. As a depo we can slow clearance from circulation using polyethylene glycol either permanently or reversible preg pegylation. As a prodrug, we can create fusion proteins using synthetic polypeptides or naturally occurring proteins such as HCG albumin and immig lobular chains. And lastly, we can modify its ability to bind to serum proteins and and one of the mechanisms is to change the binding to albumin. So, the first product that I'd like to talk about is loop peg somatropin. Um This is a once weekly drug that has been approved by the FDA in August of 2025. In the bottom cartoon, you can see that um the native unmodified growth hormone is connected to the carrier, which is a pegylated, uh a peg group by a trans con linker. And as the um molecule is injected into the body, that linker is actually cleaved dependent upon the ph and temperature releasing active growth hormone, which can then interact with the receptor and the peg and the uh linker are actually then cleared by the kidney. So this pegylated growth hormone is an inactive prodrug that is transiently linked to the trans con carrier releasing native growth hormone. So, the clinical trial that showed that, uh, lono somatropin improved growth in Children and was non inferior to daily growth hormone. Was the phase three HT trial. Um, you can see on the, um, top cart.