United States

Background: The central hypothalamic melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Certain variants in genes upstream of MC4R, including those encoding the leptin receptor (LEPR), proopiomelanocortin (POMC), steroid receptor coactivator 1 (SRC1; also known as NCOA1), prohormone convertase (PC)1/3 (encoded by the gene PCSK1), and SH2B adaptor protein 1 (SH2B1) genes, lead to impaired MC4R pathway signaling and rare genetic diseases of obesity. While the deficiencies resulting from these genetic variants differ in some clinical features, they are all characterized by hyperphagia (pathologic insatiable hunger) and early-onset obesity during childhood. Setmelanotide, an MC4R agonist, reduced body weight and hyperphagia (assessed by hunger scores) after 3 months in patients with heterozygous POMC, including patients with the N221D variant in PCSK1; LEPR; SRC1; and SH2B1 (including a 220–kilobase pair distal deletion of chromosome 16p11.2) variants in an earlier Phase 2 trial. In the Phase 2 trial, 12 of 35 (34%) patients with heterozygous POMC, PCSK1, or LEPR variants; 9 of 30 patients (30%) with heterozygous SRC1 variants; and 13 of 35 (37%) patients with heterozygous SH2B1 variants achieved ≥5% weight loss after 3 months of setmelanotide treatment.Methods: EMANATE is a randomized, double-blind, placebo-controlled Phase 3 trial (NCT05093634) comprising 5 similar independent sub-studies based on genetic variants. For eligibility, patients must be 6-65 years old, have history of hyperphagia and childhood obesity, current obesity defined as BMI ≥30 kg/m² (in those ≥18 years old), and BMI ≥95th percentile (in those 6-17 years old). Patients must also have a heterozygous genetic variant in POMC or PCSK1; heterozygous genetic variant in LEPR; a homozygous, heterozygous, or compound heterozygous variant in SRC1 or SH2B1 (including a chromosomal deletion of 16p11.2 including SH2B1); or a heterozygous N221D variant in PCSK1. Patients with ≥2% weight loss in the prior 3 months, HbA1C &gt;10%, clinically significant pulmonary, cardiac, or oncological disease, or history of significant liver or serious kidney disease are not eligible. Within each sub-study, patients will be randomized 1: 1 to receive daily subcutaneous injections of setmelanotide or placebo for 52 weeks. The primary outcome is the mean change in body weight in patients who receive setmelanotide compared with placebo. Safety will be assessed by frequency and severity of adverse events.
Current Status: EMANATE is currently underway and began enrolling patients in early 2022. The planned enrollment is 560 patients. If successful, this placebo-controlled Phase 3 trial will support setmelanotide treatment for improvements in body weight–related measures and hunger in an expanded population of patients living with rare genetic diseases of obesity.

ENDO 2022

Setmelanotide in Patients With Heterozygous POMC, LEPR, SRC1, or SH2B1 Obesity: Design of EMANATE – A Placebo-Controlled Phase 3 Trial

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Background: The central hypothalamic melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Certain variants in genes upstream of MC4R, including those encoding the leptin receptor (LEPR), proopiomelanocortin (POMC), steroid receptor coactivator 1 (SRC1; also known as NCOA1), prohormone convertase (PC)1/3 (encoded by the gene PCSK1), and SH2B adaptor protein 1 (SH2B1) genes, lead to impaired MC4R pathway signaling and rare genetic diseases of obesity. While the deficiencies resulting from these genetic variants differ in some clinical features, they are all characterized by hyperphagia (pathologic insatiable hunger) and early-onset obesity during childhood. Setmelanotide, an MC4R agonist, reduced body weight and hyperphagia (assessed by hunger scores) after 3 months in patients with heterozygous POMC, including patients with the N221D variant in PCSK1; LEPR; SRC1; and SH2B1 (including a 220–kilobase pair distal deletion of chromosome 16p11.2) variants in an earlier Phase 2 trial. In the Phase 2 trial, 12 of 35 (34%) patients with heterozygous POMC, PCSK1, or LEPR variants; 9 of 30 patients (30%) with heterozygous SRC1 variants; and 13 of 35 (37%) patients with heterozygous SH2B1 variants achieved ≥5% weight loss after 3 months of setmelanotide treatment.Methods: EMANATE is a randomized, double-blind, placebo-controlled Phase 3 trial (NCT05093634) comprising 5 similar independent sub-studies based on genetic variants. For eligibility, patients must be 6-65 years old, have history of hyperphagia and childhood obesity, current obesity defined as BMI ≥30 kg/m² (in those ≥18 years old), and BMI ≥95th percentile (in those 6-17 years old). Patients must also have a heterozygous genetic variant in POMC or PCSK1; heterozygous genetic variant in LEPR; a homozygous, heterozygous, or compound heterozygous variant in SRC1 or SH2B1 (including a chromosomal deletion of 16p11.2 including SH2B1); or a heterozygous N221D variant in PCSK1. Patients with ≥2% weight loss in the prior 3 months, HbA1C >10%, clinically significant pulmonary, cardiac, or oncological disease, or history of significant liver or serious kidney disease are not eligible. Within each sub-study, patients will be randomized 1: 1 to receive daily subcutaneous injections of setmelanotide or placebo for 52 weeks. The primary outcome is the mean change in body weight in patients who receive setmelanotide compared with placebo. Safety will be assessed by frequency and severity of adverse events.
Current Status: EMANATE is currently underway and began enrolling patients in early 2022. The planned enrollment is 560 patients. If successful, this placebo-controlled Phase 3 trial will support setmelanotide treatment for improvements in body weight–related measures and hunger in an expanded population of patients living with rare genetic diseases of obesity.

technical paper

Background: Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Monogenic obesity disorders, including CLD, have been reported to be prevalent among children with severe obesity in a consanguineous Pakistani population. Targeted therapy is available in the form of recombinant human leptin (metreleptin). We previously reported baseline characteristics of the first cases of CLD identified in the United States, sisters of Pakistani origin with a family history of consanguinity. This report provides follow-up after 18 months of metreleptin therapy in an observational research protocol.

Clinical Case: Two sisters ages 18 yrs (A; BMI 45.2 kg/m2) and 20 yrs (B; 45.0 kg/m2) were referred for evaluation of obesity. Both had hyperphagia and excessive weight gain by age 3 months. They had been treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. Sister A was diagnosed with type 2 diabetes at age 15 years and was treated with metformin and liraglutide with suboptimal glycemic control (HbA1C 9.3%). At the time of their initial evaluation, serum leptin levels were undetectable. After discontinuing OCPs, testing confirmed hypogonadotropic hypogonadism. Both patients were homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. Treatment was initiated with metreleptin 5 mg daily SC in Sister A and 3.75 mg SC daily, increasing to 5 mg daily at Week 8 in Sister B. Both remained on therapy throughout the 18 month observational trial without serious adverse effects or clinical evidence of neutralizing antibodies. At study end, both had substantial weight loss (Sister A: 45.3 kg or 32.8% of initial weight, Sister B: 39.1 kg or 33.1% of initial weight). Clinically significant improvements in related parameters were observed, including percent body fat (Sister A: -13%, Sister B: -18%), HOMA2-IR (A: -83% , B: -80% ), ALT (A: -90%, B: -91%), triglycerides (A: -47%, B: -26%), hsCRP (A: -80%, B: -84%), FGF-21 (A: -81%, B: -67%), and adiponectin (A: +42%, B: +37%). In both sisters, hepatic steatosis improved and bone mineral density increased (A: +0.7 SD, B: +0.6 SD). At study end, Sister A's HbA1C was 5.4% off medication. Spontaneous regular menses resumed after 3 months of therapy in Sister A and four months in Sister B. Improvements were observed in mood, self-esteem, physical function, energy, quality of life, dietary disinhibition, and perceived hunger, measured by validated questionnaires.

Conclusion: Metrelepin produced significant improvements in weight, metabolic profiles, hepatic steatosis, reproductive function, mood and quality of life in our patients. Given the efficacy of metreleptin therapy, screening for CLD should be undertaken for any patient presenting with hyperphagia and early onset of obesity.

Congenital Leptin Deficiency: Metabolic, Reproductive, and Psychological Impacts of Therapy

Introduction
Changes in the expression of microRNA facilitate in the formation of various tumors. MEN1 is a rare disease caused by mutations in MEN1 gene encoding the menin protein and characterize by the occurrence of parathyroid, pituitary, gastroenteropancreatic and other tumors. If a patient with the MEN1 phenotype carry no mutations in the MEN1 gene, the condition considers a phenocopy of syndrome (phMEN1). We hypothesize that the pathogenic link among the above sporadic tumors might be represented by molecular pathways involving the MEN1 gene and epigenetic regulations — particularly microRNAs.
Materials & methods
Single-center, case-control study: assessment of plasma microRNA expression in patients with phMEN1, acromegaly (AM), primary hyperparathyroidism (PHPT) and healthy controls. Morning plasma samples were collected from fasting patients and age- and sex-matched controls and stored at –80°C. Total RNA isolation: miRNeasy Mini Kit with QIAcube. The libraries were prepared by the QIAseq miRNA Library Kit following the manufacturer. Circulating miRNA sequencing was done on Illumina NextSeq 500 (Illumina). Subsequent data processing was performed using the DESeq2 bioinformatics algorithm.
Results
We enrolled 36 consecutive patients (12 patients in each group) with phMEN1, AM, PHPT, along with 12 age and gender matched controls. Median age of phMEN1 group — 59 [52; 60.5]; AM — 59 [52; 63]; PHPT — 60.5 [54; 62.5]; control — 59 [51.5; 62.5]. The groups did not differ in age (p=0.88) and gender – in all groups were 11 women and 1 man (p=1.00).
We divided all assessed microRNAs into 3 groups based on the significance of the results; the first group consisted of samples with the highest levels of detected microRNAs (>50), the second group — moderate (10–50), the third group — the lowest (<10).
The microRNA expression pattern was almost the same between AM and phMEN1 groups (15 microRNAs upregulated, 10 — downregulated), we found slightly decreased hsa-miR-4301 (padj=0.038); it is interesting that phMEN group when compared to PHPT and control groups showed decline in hsa-miR-4301 too. PHPT and control groups had also quite similar expression profile (4 microRNAs upregulated, 19 — downregulated).
607 microRNA were differently expressed in groups phMEN1 and PHPT (473 upregulated microRNAs, 134 — downregulated). We found increased expression of some microRNAs that interferes with menin: hsa-miR-24-1-5p (padj=0.0008), hsa-miR-24-3p (padj=0.034), hsa-miR-26a-5p (padj=0.0005), hsa-miR-421 (padj=0.018), hsa-miR-762 (padj=0.027). In addition, we found decreased microRNAs with oncogene potential: miR-3182 (padj=0.007), hsa-miR-875-5p (padj<0.001), hsa-miR-6749-5p (padj<0.001).
173 microRNA differed in phMEN1 and control groups (11 microRNAs upregulated, 162 — downregulated). We detected several decreased microRNAs in phMEN1 that participate in tumor genesis: hsa-miR-625-3p (padj<0.005), hsa-miR-3168 (padj=0,028), hsa-miR-302b-3p (padj<0.001).
Conclusion
We found microRNAs, which could potentially become biomarkers in phMEN1 diagnosis. The results need to be validated using different measurement method with larger sample size. Likewise further assessment of plasma microRNA expression in genetically confirmed MEN1 patients is needed.

Plasma MicroRNA Expression in Phenocopy of Multiple Endocrine Neoplasia Type 1 Compared to Patients with Acromegaly and Primary Hyperparathyroidism: Potential Biomarkers of Multiple Endocrine Tumor Growth

Background: Differential diagnosis of hyponatremia is challenging, particularly for thiazide associated hyponatremia (TAH), as patients might have either volume depletion in need for fluid substitution or syndrome of inappropriate antidiuresis (SIAD)-like presentation requiring fluid restriction. Urine indices are of little utility, because they are influenced by thiazide therapy. Apparent strong ion difference (aSID) describes the relation between sodium, potassium and chloride in serum and is used in evaluation of acid-base disorders according to Stewart model. aSID could help in the differential diagnosis of TAH because a value >40 identifies patients with contraction alkalosis due to relative hypochloremia, and hypochloremic alkalosis is a well-known possible adverse effect of thiazide diuretics.
Material and Methods: This was a post-hoc analysis of prospectively collected data of hospitalized patients with hypotonic hyponatremia <125 mmol/l. TAH patients were divided according to treatment response in patients needing intravenous fluid substitution or fluid restriction. Treatment response was defined as a sodium increase of at least 4 mmol/l/die or >130 mmol/l based on chart review. aSID at baseline was calculated with the formula serum sodium plus potassium minus chloride and a value >40 was used to identify volume-depleted TAH patients. Descriptive analysis was carried out to find differences between volume-depleted and SIAD-like TAH patients, and patients with SIAD without thiazide use. Logistic regression and ROC curves were computed to investigate the role of aSID>40 for differential diagnosis of hyponatremia in TAH patients, in addition to known factors for identifying SIAD patients as body mass index (BMI) and fractioned uric acid excretion (FUA) with the previous described cut-off of 12%.
Results: Out of 303 hyponatremia patients, 131 (43.2%) had a TAH and 75 (24.8%) SIAD without thiazide use. Among TAH patients, 81 (61.8%) were successfully treated with fluid substitution and 31 (23.7%) with fluid restriction. 19 patients (14.5%) were excluded as they received no treatment, or needed to switch treatment during hospitalization. No differences in baseline characteristics were seen between patients with SIAD and SIAD-like TAH patients, except for BMI, lower in SIAD patients (mean(SD) 23.5(5.1) vs 27.0(5.7) kg/m2, p=0.003). A higher BMI and a FUA<12% had a sensitivity of 84% with a specificity of 60% in identifying volume-depleted TAH patients. Adding aSID>40 improved the specificity to 74% maintaining a sensitivity to 82%.
Conclusion: In hospitalized patients with TAH, calculation of aSID may help differentiating patients with volume depletion in need of fluid substitution from SIAD-like manifestation requiring fluid restriction.

Role of Apparent Strong Ion Difference in the Differential Diagnosis of Thiazide Associated Hyponatremia

Background: Aneurysms of the internal carotid arteries are a rare cause of pituitary dysfunction1. While there are reports of primary amenorrhea in females due to ectatic internal carotid arteries2, hypogonadism in a male due to "kissing internal carotid arteries" causing compression of the pituitary gland has not previously been reported.
Clinical Case: A 27-year-old male with history of Crohn's disease, obesity, depression and sleep apnea on CPAP presented to endocrinology clinic for evaluation of low testosterone levels diagnosed 9 months prior to his initial visit. At the time of initial evaluation patient was using intramuscular testosterone cypionate 120mg weekly with total testosterone of 2.43 ng/mL (2.50-9.50 ng/mL). Testosterone replacement therapy was discontinued at that time to assess the hypothalamic-pituitary-gonadal (HPG) axis. After 9 months without testosterone treatment, repeat labs demonstrated total testosterone 0.91 ng/mL, bioavailable testosterone 0.69 ng/mL (1.10-4.0 ng/mL), SHBG 8 nmol/L (10-89 nmol/L), LH 3.1 mIU/mL (2-12 mIU/mL), FSH 2.7 mIU/mL (1.5-10 mIU/mL), estradiol 23 pg/mL (6-44 pg/mL), IGF-1 193 ng/mL (85-310 ng/mL), prolactin 10 ng/mL (3-23 ng/mL), TSH 1.03 mIU/L (0.3-5.5 mIU/L), FT4 1.15 ng/dL (0.76-1.70 ng/dL), 8 AM cortisol 13.5 ug/dL (5.3-22.5 ug/dL) and ACTH 37 pg/mL (5-52 pg/mL). Semen analysis was also performed which was unremarkable. Pituitary MRI revealed symmetric ectatic cavernous portions of the internal carotid arteries compressing and distorting the normal anatomy of the anterior pituitary gland consistent with "kissing carotid arteries." MRA was performed which did not demonstrate aneurysm or malformation of the cavernous internal carotid arteries. Patient was started on subcutaneous semaglutide 0.25mg weekly which was titrated to 1mg weekly for treatment of obesity. Testosterone replacement therapy was not re-initiated given future fertility goals and normal semen analysis.
Conclusion: To our knowledge, this is the first reported case of kissing internal carotid arteries causing isolated hypogonadotropic hypogonadism in a male patient.
References
1) Heshmati HM, Fatourechi V, Dagam SA, Piepgras DG. Hypopituitarism caused by intrasellar aneurysms. Mayo Clin Proc. 2001 Aug;76(8): 789-93. doi: 10.1016/S0025-6196(11)63222-9. PMID: 11499817
2) Sahin M, Dilli A, Karbek B, Unsal IO, Gungunes A, Colak N, Uçan B, Cakal E, Ozbek M, Delibasi T. Unusual cause of primary amenorrhea due to kissing internal carotid arteries. Pituitary. 2012 Jun;15(2): 258-9. doi: 10.1007/s11102-012-0393-9. PMID: 22492265.

Kissing carotid arteries: An unusual cause of male hypogonadotropic hypogonadism.

Background: Patients with hypopituitarism can have a complete or partial deficiency of pituitary hormones. If not treated adequately, it can result in episodes of myxedema coma or adrenal crisis. Our patient was unique with findings of both myxedema coma and adrenal crisis together on initial presentation.
Clinical Case: A 35-year-old female with a medical history of Sheehan's Syndrome, transient diabetes insipidus and lyme carditis presented to the emergency department with dizziness, lethargy, and generalized weakness for 1 day. EMS found her blood glucose level to be 21. The patient was given oral glucose. In the ED, her blood glucose level was found to be 34. She confessed she had been noncompliant with her medications for a month. She had no other complaints or possible precipitating factors including illness/trauma/stress. On admission, she was found to be hypothermic to 91.3 deg F, bradycardic to 40-50s, and hypotensive (Systolic 80s-90s/diastolic 50s-60s). On physical examination, she was thin and lethargic but oriented. No gross focal neurological deficits were noted. In addition to the initial hypoglycemia, her laboratory findings were significant for a TSH level of 0.52, T3 level of <30, T4 level of <0.5, eosinophilia as well as normal sodium levels. The sepsis workup was negative. Her VBG showed mild respiratory acidosis. For the myxedema coma and adrenal crisis, she was initially given hydrocortisone 100 mg and levothyroxine 200mcg. Her hypoglycemia improved after administration of these medications and intravenous fluids of dextrose-normal saline. The endocrinology service was consulted, and the patient was admitted to the ICU for monitoring. The next day her hypothermia, hypotension resolved and her lethargy, weakness improved. Once she was stabilized in the ICU, she was transferred to the floors. For the myxedema coma, once stable, she was started on oral levothyroxine 100mcg in accordance with weight-based dosing (1.6 mcg/kg daily) on the following day. Her free T4 level improved from 0.48 to 0.56 to 0.72. Her T3 level improved from <30.0 to 42.7. For the adrenal crisis, after the initial dose of IV hydrocortisone 100mg, it was tapered down to IV hydrocortisone 50 mg, then switched to oral prednisone daily. Eosinophilia from admission was mild which resolved later. Additional management of her history of Sheehan's Syndrome, her levels of LH 0.5, FSH 1.2, Estradiol <5, and Prolactin 0.6 were all low, so was advised to follow up with hormone replacement therapy outpatient.
Conclusion: This is an interesting case presentation of myxedema coma and adrenal crisis in a patient with a history of Sheehan's Syndrome. It is important to consider the unique and similar presentations of both myxedema coma and adrenal crisis such as hypotension, bradycardia, hypothermia, hypoglycemia, and lethargy.

Unique Case of Combined Presentation of Myxedema Coma and Adrenal Crisis in a Patient With Hypopituitarism or Post Sheehan's Syndrome

The anterior pituitary controls growth, metabolism, reproduction and stress responses through the synthesis and secretion of specific hormones. Distinct cell lineages within the anterior pituitary generate specific hormones. Interestingly, the anterior pituitary exhibits a high level of adult cell plasticity that allows committed hormone-producing cells to alter their cell fate and produce different hormones to meet altered organismal demands. The molecular mechanisms underlying this adult cell plasticity have not been fully characterized. Our recent work has implicated the stem cell determinant and sequence-specific mRNA binding protein, Musashi, as a regulator of pituitary cell plasticity. The mechanisms by which Musashi controls pituitary cell plasticity are unknown. In this study, we have sought to identify the mRNA regulatory targets of Musashi in the adult mouse pituitary. Through the use of Musashi-RNA-immunoprecipitation we report a cohort of 1192 pituitary mRNAs that specifically interact with Musashi. mRNAs specific to each of the hormone-producing cell lineages were identified, as well as mRNAs specific to immature stem and progenitor cell lineages. The biological pathways encoded by the Musashi-enriched mRNAs include cell adhesion, cellular homeostasis, unfolded protein responses, protein trafficking, endocrine processes and female pregnancy. Functional analysis of validated mRNAs reveals both activating and inhibitory control of mRNA translation by Musashi. Together, our findings indicate a broad and complex role for Musashi in the post-transcriptional regulation of adult pituitary function.

Insight into Integrated Control of Pituitary Function Revealed Through Analysis of Musashi Target mRNAs

Medical treatment of acromegaly is based on either suppressing pituitary GH secretion or inhibiting GH action by preventing interaction with its receptor in order to suppress the elevated levels of IGF1. AZP-3813 is a 16-amino acid, bicyclic peptide antagonist of the GH receptor (GHR) with a KD of 1.9nM for the human GHR, and 18.5nM for the rat GHR. The circulating half-life of AZP-3813 in the rat is 11.2 hours. In previous studies, AZP-3813 was demonstrated to suppress IGF1 secretion in juvenile rats in a dose-related manner, and to maintain IGF1 suppression when given over 4 days. To examine the ability of chronic AZP-3813 treatment to maintain suppression of IGF1 levels, we injected normal, 5-week old (~150g), male Sprague Dawley rats subcutaneously either with vehicle or with AZP-3813 at doses of either 10 or 30mg/kg QD for 19 days (n=7/group). Blood samples were collected immediately prior to either vehicle or AZP-3813 injection on days 1, 2, 3, 7, 10, 15 and 19, and 24h after the last injection (day 20). Samples were assayed for total IGF1 content by radioimmunoassay, and samples collected on days 2, 10 and 19 were also analyzed for AZP-3813 content by LC-MS/MS. At the initiation of treatment, the average body weight of the rats was 150.3 + 3.0g, and over the 20 days of the study animals treated with vehicle gained an average of 158.4 + 4.9g. In contrast, rats treated QD with 10 or 30mg/kg AZP-3813 gained 23.6 + 2.1 and 27.9 + 2.2% less weight than the vehicle-treated controls, respectively. Accumulation of AZP-3813 levels in the blood was observed with repeated daily injections of both 10 and 30mg/kg, increasing from day 2 levels by 107.1 + 12.5 and 125.2 + 36.3%, respectively, by day 19. In the vehicle-treated control rats, IGF1 levels increased from an initial 395.1 +16.3ng/ml to 674.4 + 19.8ng/ml by day 20. Twenty-four hours after the first injections of 10 and 30mg/kg AZP-3813, IGF1 levels were suppressed by 27.6 + 3.4 and 29.2 + 3.3%, respectively, versus vehicle-treated control levels, and, with continued treatment, a similar magnitude of IGF1 suppression was maintained through day 20 despite the progressively increasing levels of IGF1 observed in the vehicle-treated rats. At study termination on day 20, animals treated with 10 and 30mg/kg AZP-3813 were observed to have 4.1 and 4.6% shorter femur length, 1.1 and 3.6% shorter body length, and 7.7 and 13.3% less liver weight, respectively, as compared with vehicle-treated control rats. These results demonstrate that with continued treatment, the potent GHR antagonist activity exhibited by AZP-3813 translates to sustained in vivo suppression of IGF1 levels and associated parameters, and support its development as a potential therapy for acromegaly.

Sustained Suppression of IGF1 with AZP-3813, a Bicyclic 16-Amino Acid Peptide Antagonist of the Human Growth Hormone Receptor and a Potential New Treatment for Acromegaly

Introduction:
Diabetes insipidus (DI) is a rare complication of subarachnoid hemorrhage (SAH) and associated with worse prognosis and increased mortality. We present a case of combined nephrogenic and central DI together with osmotic diuresis as a result of SAH and discuss the pathophysiology.
Case:
A 63-year-old female without significant past medical history was found unresponsive. CT head followed by angiography confirmed extensive SAH arising from a saccular anterior communicating artery (Acoma) aneurysm. She underwent emergent coil embolization and right frontal external ventriculostomy drain placement. Postoperatively, she developed polyuria (300-400 mL/hour) and hypernatremia (156 mEq/L) concerning for the development of DI. Serum osmolality was elevated at 316 mOsm/kg, urine osmolality inappropriately low relative to serum osmolality at 289 mOsm/kg but also unexpectedly high for complete DI, serum potassium 2.9 mEq/L and urine potassium elevated urine at 9 mEq/L. Serum copeptin was 6 pmol/L and inappropriately low for nephrogenic DI, suggesting a mixed central and peripheral process as well as contribution from osmotic diuresis. Intravenous (IV) desmopressin (DDAVP) only slightly reduced the polyuria. Management was complicated by adypsia and persistent hypokalemia requiring ongoing replacement. IV fluid, which had initially consisted of high-osmolality Plasma-Lyte (294 mOsm/L), matched to urine output, was switched to D5W, leading to a significant decrease in polyuria. On post-operative day 17, DDAVP was discontinued with normalization of sodium (137 mEq/L), potassium (3.8 mEq/L) and urine output. Three months post-operatively, she was asymptomatic with intact pituitary function and no hypokalemia.
Discussion:
Hypokalemia in patients with SAH is thought due to acute intracellular shift of potassium caused by excessive β2-adrenergic activity generated endogenously by the sympathetic nervous system. In our patient, there was also likely contribution from distal tubular delivery of sodium from osmotic diuresis, leading to increased urinary potassium losses and hypokalemia-induced partial nephrogenic DI which was further complicated by partial central DI as suggested by the inappropriately low copeptin level for nephrogenic DI in face of a high serum osmolality and inappropriately low urine osmolality. As the vascular supply to anterior hypothalamus is derived from the Acoma, rupture may compromise perfusion affecting neuronal populations in the lamina terminalis that regulate thirst and AVP secretion in response to hyperosmolarity. Early detection of DI is critical because hypovolemia can predispose to cerebral vasospasm and worsen outcomes. This case also depicts the importance of careful consideration of sources of osmolar loads such as the composition of administered IV fluids, and aggressive potassium replacement to maintain DDAVP sensitivity.
Conclusion:
DI should be considered in polyuria syndrome with hypernatremia after a neurosurgical event. Nephrogenic and central DI and adypsia can manifest following SAH, with sources of iatrogenic osmolar load further complicating the clinical picture. Early recognition and treatment may reduce morbidity and mortality.

Subarachnoid Hemorrhage Complicated by Nephrogenic and Central Diabetes Insipidus

Background
Once-weekly lonapegsomatropin (TransCon hGH) is a long-acting prodrug of somatropin, recently approved for the treatment of pediatric growth hormone deficiency (GHD) by the US FDA. In the pivotal 52-week phase 3 heiGHt trial and the 26-week fliGHt trial, lonapegsomatropin demonstrated safety and efficacy in both treatment-naïve and treatment-experienced children with GHD.
Methods
Results are reported from Week 130 (data snapshot date: September 01, 2021) from the open-label extension trial enliGHten. Upon entry into enliGHten, all participants received lonapegsomatropin via vial/syringe, with subsequent switch to TransCon hGH Auto-Injector when available.
Results
A total of 298 participants (98% of parent trials) continued from the heiGHt or fliGHt trials into enliGHten. At Week 130, 36 participants had completed the trial and 248 participants remain enrolled. The height standard deviation score (SDS) mean (standard deviation [SD]) at Week 130 was -0.64 (0.85) compared with baseline value of -1.56 (0.88) at the start of enliGHten. Participants continued to approach the average parental height SDS mean (SD) of -0.39 (0.77). The annualized height velocity mean (SD) at Week 130 was 9.32 cm/year (0.45). Average IGF-1 SDS mean (SD) at Week 130 was 1.46 (1.18) compared with 0.52 (1.58) at enliGHten baseline. For the 36 participants who had completed the trial, 14 had reached bone age of >14 years (girls) or >16 years (boys), and 24 had completed the study based on investigator judgement that treatment for growth hormone deficiency was no longer necessary. The difference between mean (SD) height SDS at last visit and average parental height SDS was -0.05 (0.75) for the 36 completers, and 61.1% of these participants had met or exceeded the average parental height SDS. The mean (SD) total duration of hGH treatment for participants who completed the trial (including daily treatment and lonapegsomatropin) was 3.53 (0.88) years, and the mean (SD) duration of treatment with lonapegsomatropin was 2.20 (0.66). With continued lonapegsomatropin treatment, the AE profile remained consistent with what was observed in the parent trials, with no new safety signals.
Conclusions
Children and adolescents treated with lonapegsomatropin showed continued improvement of height SDS through their 3rd year of therapy. Lonapegsomatropin continued to demonstrate a safety profile comparable to that of daily somatropin therapy.

Safety and Efficacy of Treatment with Lonapegsomatropin in Children with Growth Hormone Deficiency at Week 130 in the enliGHten Trial

BACKGROUND:
Somatrogon is a long-acting recombinant human growth hormone (hGH) currently in development as a once-weekly injectable treatment for children with growth hormone deficiency (GHD). In a phase 2 (NCT01592500) and a phase 3 (NCT02968004) study, patients received either once-weekly somatrogon or once-daily Genotropin.

AIMS:
Compare the phase 2 and 3 study results with growth data from published literature and a database of children treated with once-daily Genotropin.

METHODS:
In the 12-month main portion of the phase 2 study (004), patients were randomized to 1 of 3 once-weekly somatrogon doses (0.25, 0.48, and 0.66 mg/kg/week) or once-daily Genotropin (0.24 mg/kg/week). After the main portion of 004, patients continued into the open-label extension (OLE), consisting of an additional 12 months at the original somatrogon dose (Genotropin recipients were randomized to 1 of the 3 somatrogon dose regimens), after which all patients received somatrogon at 0.66 mg/kg/week. In the 12-month main portion of the phase 3 study (006), patients were randomized to once-weekly somatrogon (0.66 mg/kg/week) or once-daily Genotropin (0.24 mg/kg/week). After the main portion of 006, all patients received somatrogon (0.66 mg/kg/week) in an OLE. Four year growth data from 004 and 006 were pooled and analyzed, then compared with growth data from matched subsets of hGH-treated patients as reported by Ranke and Lindberg1 (Genotropin dose: 0.22-0.31 mg/kg/week) and Bakker et al,2 (hGH dose: most patients received 0.3 mg/kg/week) and with data from a matched cohort from the Pfizer International Growth Study Database (KIGS), in which patients received once-daily Genotropin (0.20-0.28 mg/kg/week).

RESULTS:
The combined mean height velocity (HV) at the end of the 12-month main portions of study 004 and 006 was 10.37 cm/year for somatrogon-treated patients. The Year 1 mean HV reported by Ranke and Lindberg for children with a chronological average-centered age of 7.5 years was 9.4 cm/year and 8.3 cm/year for children with severe and moderate GHD, respectively. The Year 1 mean HV reported by Bakker et al for children with idiopathic GHD aged 7.5 years at the beginning of hGH therapy was ~10 cm/year (for males and females). The mean annual HVs during the OLE period were 9.37, 8.97, and 9.03 cm/year at OLE Year 1, 2 and 3 in somatrogon-treated patients, which were numerically greater than HVs of 7.09, 6.35, and 6.08 cm/year at the corresponding annual visit in the matched KIGS cohort (Genotropin dose: 0.20–0.28 mg/kg/week).

CONCLUSIONS:
Comparisons with published literature and the KIGS database indicate that children treated with once-weekly somatrogon (0.66 mg/kg/week) showed good growth, compared with children treated with once-daily hGH, strengthening the expectation that somatrogon-treated children are likely to achieve a satisfactory final adult height.

References
1.Ranke and Lindberg. JCEM. 2010;95(3): 1229-1237.
2.Bakker, Frane, et al. JCEM. 2008;93(2): 352-357.

Growth outcomes from the phase 2 and phase 3 studies of once weekly somatrogon vs daily genotropin in pediatric patients with growth hormone deficiency: comparisons with published literature and an international growth study database

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