Background:Adherence to type 1 diabetes mellitus (T1DM) treatment regimens decreases during adolescence. While comorbid depression and health insurance disparities are individually known to potentiate this risk, technological devices for T1DM appear to be protective. Objective:We examined whether technology use impacted the association between depression and poorer health outcomes in T1DM. Given established insurance-based disparities based on technology access, we also studied whether the protective effects of T1DM technology differed among publicly and privately insured youth. Methods:Data were prospectively collected from pediatric patients with T1DM across 3 California medical centers. We used linear and negative binomial regression analyses to examine whether technology use was related to diabetes outcomes and whether this differed based on depression status (technology-by-depression interaction) and health insurance type (technology-by-insurance interaction). Results:Across 1573 patients aged 12 to 25 years (mean age 15.9, SD 2.9 years; n=1050, 66.4%, non-Hispanic White; n=745, 47.0% female), those with a depression diagnosis had higher hemoglobin A1c (HbA1c; mean 9.1%, SD 2.1% vs 10.1%, SD 2.2%) and more frequent diabetic ketoacidosis (DKA) events per year (mean 0.10, SD 0.36 vs 0.24, SD 0.66) than those without (P=.003). Patients using both a continuous glucose monitor (CGM) and pump had lower HbA1c levels and fewer DKA events per year (mean HbA1c 8.2%, SE 0.1%; mean DKA events per year 0.05, SE 0.01) than those using one device (mean HbA1c 9.0%, SE 0.1%; mean DKA events 0.08, SE 0.1%) or none (mean HbA1c 10.0%, SE 0.1%; mean DKA events 0.19, SE 0.1%; P<.001). While youth with public insurance had significantly higher HbA1c levels than those with commercial insurance (mean 9.3%, SD 2.1% vs 9.0%, SD 2.0%, P<.001), those using a CGM had no reliable decrease in HbA1c compared to their commercially insured peers (P=.35). Conclusions:Technology use in pediatric T1DM appears protective for both youth with a history of depression and those who are publicly insured. These data underscore the importance of universal access to technology to mitigate disparities based on comorbid mental health issues and differential access to care.

Background Hypothalamic obesity resulting from hypothalamic damage might affect melanocortin signalling. We investigated the melanocortin-4 receptor agonist setmelanotide for treatment of hypothalamic obesity. Methods This phase 2, open-label, multicentre trial was done in five centres in the USA. Eligible patients were aged between 6 and 40 years with obesity and history of hypothalamic injury or diagnosis of a non-malignant tumour affecting the hypothalamus that was treated with surgery, chemotherapy, or radiation. Setmelanotide was titrated up to a dose of 30 mg and administered subcutaneously once a day for a total duration of 16 weeks. The primary endpoint was the proportion of patients with a reduction in BMI of at least 5% from baseline after 16 weeks, compared with a historic control rate of less than 5% in this population. The primary endpoint was analysed using the full analysis set, which includes all patients with baseline data who received at least one dose of setmelanotide. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04725240) and is complete. Finding Between June 6, 2021, and Jan 13, 2022, 19 patients were screened for inclusion. One patient was excluded, and 18 were enrolled and received at least one dose of setmelanotide. Patients were primarily White (n=14 [78%]) and male (n=11 [61%]). Enrolled patients had a mean age of 150 years (SD 53) and a mean BMI of 380 kg/m(2) (SD 65). Of 18 patients enrolled, 16 (89%) of 18 patients completed the study and met the primary endpoint of reduction in BMI of at least 5% from baseline after 16 weeks (p<00001). The mean reduction in BMI across all patients was 15% (SD 10). A composite proportion of patients had a clinically meaningful change (89%, 90% CI 69-98%; p<00001), comprising a reduction in BMI Z score of at least 02 points for patients younger than 18 years (92%, 68-100%; p<00001) and reduction in bodyweight of at least 5% for patients aged 18 years or older (80%, 34-99%; p<00001). Patients aged 12 years or older had a mean reduction in hunger score of 45%. Frequent adverse events included nausea (61%), vomiting (33%), skin hyperpigmentation (33%), and diarrhoea (22%). Of 14 patients who continued treatment in a long-term extension study (NCT03651765), 12 completed at least 12 months of treatment at the time of publication and had a mean change in BMI of -26% (SD 12) from index trial baseline. Interpretation These findings support setmelanotide as a novel effective treatment of hypothalamic obesity.

Neonatal Graves disease is the most common cause of hyperthyroidism during the newborn period. Maternal Graves disease increases the risk of intrauterine growth restriction, small for gestational age, and neonatal Graves disease. Intrauterine growth restriction and small for gestational age are associated with hypoglycemia and transient neonatal hyperinsulinism. Neonatal Graves disease with severe persistent hypoglycemia has not been well described. We present the case of a female patient born at 34 weeks and 3 days with a birth weight of 1.6 kg (fifth percentile) to a mother with recent treatment for Graves disease. Prenatal ultrasounds were significant for intrauterine growth restriction and small for gestational age. The mother did not begin hyperthyroidism medical therapy until 23 weeks and 2 days of gestation. After the infant was born, the infant not only had symptoms of hyperthyroidism such as tachycardia and abnormal thyroid values but also had persistent hypoglycemia, which could be due to maternal propranolol usage, prematurity, IUGR, increased metabolism due to neonatal Graves, and transient stress-induced hyperinsulinism. The infant was started on methimazole for hyperthyroidism and propranolol for tachycardia. She was also started on diazoxide for persistent hypoglycemia. By 6 months of age, the hyperthyroidism and hypoglycemia had resolved. This is an interesting case of neonatal Graves disease with severe persistent hypoglycemia which we suspect is due to transient neonatal hyperinsulinism induced by multiple stress responses.

Type 1 diabetes (T1D) is a prototypic T cell-mediated autoimmune disease. Because the islets of Langerhans are insulated from blood vessels by a double basement membrane and lack detectable lymphatic drainage, interactions between endocrine and circulating T cells are not permitted. Thus, we hypothesized that initiation and progression of anti-islet immunity required islet neolymphangiogenesis to allow T cell access to the islet. Combining microscopy and single cell approaches, the timing of this phenomenon in mice was situated between 5 and 8 wk of age when activated anti-insulin CD4 T cells became detectable in peripheral blood while peri-islet pathology developed. This "peri-insulitis," dominated by CD4 T cells, respected the islet basement membrane and was limited on the outside by lymphatic endothelial cells that gave it the attributes of a tertiary lymphoid structure. As in most tissues, lymphangiogenesis seemed to be secondary to local segmental endothelial inflammation at the collecting postcapillary venule. In addition to classic markers of inflammation such as CD29, V-CAM, and NOS, MHC class II molecules were expressed by nonhematopoietic cells in the same location both in mouse and human islets. This CD45- MHC class II+ cell population was capable of spontaneously presenting islet Ags to CD4 T cells. Altogether, these observations favor an alternative model for the initiation of T1D, outside of the islet, in which a vascular-associated cell appears to be an important MHC class II-expressing and -presenting cell.

Abstract Disclosure: C.L. Roth: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. A.H. Shoemaker: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc., Saniona. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. M. Gottschalk: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. J. Miller: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. G. Yuan: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. S. Malhotra: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. C. Scimia: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. M.J. Abuzzahab: Consulting Fee; Self; Pfizer, Inc., Consynance, Rhythm Pharmaceuticals, Inc., Endo Pharmaceuticals. Background: Hypothalamic obesity (HO) is an acquired form of severe obesity that can occur following surgical resection or radiotherapy of brain tumors. Multiple factors associated with the development of HO—including degree of hypothalamic damage from tumor treatment, comorbidities (eg, pituitary deficiencies), polypharmacy used to treat comorbidities, and unique pathophysiology—confer treatment challenges; HO is often unresponsive to lifestyle modifications and traditional obesity pharmacotherapies. In a Phase 2, 16-week trial of setmelanotide in patients with HO, 16 of 18 patients (88.9% [90% confidence interval, 69.0%-98.0%]; P<0.0001) achieved ≥5% body mass index (BMI) reduction from baseline, with a mean percent BMI change of −15.4% in patients adhering to treatment (n=17). We assessed patient histories (ie, tumor treatments, prior attempts to lose weight, and comorbidities) reported in the trial to further characterize this patient population. Methods: Patients aged ≥6 to ≤40 years with documented evidence of HO were enrolled in an open-label Phase 2 trial (NCT04725240) and received setmelanotide once daily for 16 weeks. The primary endpoint was the proportion of patients with ≥5% BMI reduction from baseline at Week 16. Tumor treatments, prior attempts to lose weight, and comorbidities are summarized narratively. Results: Eighteen patients with HO (age range, 6-24 years) were treated with setmelanotide. HO was diagnosed in patients following treatment of craniopharyngioma (n=14), hamartoma (n=3), or juvenile pilocytic astrocytoma (n=1). Six patients (33.3%) had tumor recurrence and/or multiple tumor treatments. Thirteen patients (72.2%) reported prior lifestyle modifications (ie, calorie restriction [n=4], low-carbohydrate diet [n=6], dietary tracking/modification [n=4], food access restriction [n=1], personal training [n=1]) and/or pharmacotherapy use (ie, exenatide [n=3], semaglutide [n=1], liraglutide [n=2], metformin [n=2], methylphenidate [n=2], dextroamphetamine [n=1], lisdexamfetamine [n=2], naltrexone [n=3], oxytocin [n=3], phentermine [n=1]) without substantial benefit. Comorbidities occurring in ≥25% of patients were diabetes insipidus (n=14), hypothyroidism (n=14), growth hormone deficiency (n=11), adrenal insufficiency (n=10), hypogonadism (n=8), pan/hypopituitarism (n=8), psychiatric disorders (n=8), vision problems (n=6), gastrointestinal symptoms (n=6), obstructive sleep apnea (n=5), and hypothalamic-pituitary disorder (n=3). All patients adhering to treatment (n=17, including those with pituitary deficiencies and common comorbidities)) experienced BMI reductions with setmelanotide. Conclusions: Despite complex medical histories, hypothalamic damage, and various prior failed interventions, setmelanotide reduced BMI in patients with HO in a Phase 2 trial. Presentation: Friday, June 16, 2023

Abstract Disclosure: C.L. Roth: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. A.H. Shoemaker: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc., Saniona. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. M. Gottschalk: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc. Consulting Fee; Self; Rhythm Pharmaceuticals, Inc. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. J.L. Miller: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. G. Yuan: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. S. Malhotra: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. C. Scimia: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. S. McCormack: None. M.J. Abuzzahab: Consulting Fee; Self; Pfizer, Inc., Rhythm Pharmaceuticals, Inc., Consynance. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc., Ascendis, NovoNordisk, Levo Pharmaceuticals, Lumos, Saniona, and Soleno. Background: Damage to the hypothalamus via physical trauma, tumors, surgical resection, and/or radiotherapy can impair the melanocortin signaling pathway and reduce energy expenditure, potentially leading to hypothalamic obesity, a severe form of obesity with no current specific therapeutic option. Recently, the selective melanocortin-4 receptor agonist setmelanotide demonstrated reduction in weight and hunger for patients with hypothalamic obesity who were treated in a Phase 2 trial. We describe the study design of a planned double-blind, randomized, placebo-controlled, Phase 3 trial of setmelanotide in patients with hypothalamic obesity. Methods: Approximately 120 patients will be enrolled across ≤35 sites globally. Eligibility criteria include age ≥4 years with documented evidence of acquired hypothalamic obesity with associated weight gain before and/or with tumor treatment and body mass index (BMI) ≥30 kg/m2 (≥18 years) or BMI ≥95th percentile (≥4 to <18 years). Key exclusion criteria include diagnosis of syndromic obesity, weight or BMI loss >2% based on age in the prior 3 months, bariatric surgery within the past 2 years, glycated hemoglobin >11.0%, and glomerular filtration rate <30 mL/min/1.73 m2. Patients will be randomized 2:1 and stratified by age to receive setmelanotide or placebo. Setmelanotide will be titrated over 2-8 weeks to a maximum daily subcutaneous dose of 1.5-3.0 mg based on age and weight. Double-blind treatment will continue for up to 60 weeks, with visits (in-clinic, at-home, or telehealth) at Weeks 20, 28, 36, 44, and 52 and at an end-of-treatment clinic visit at Week 60. The primary endpoint is the mean percent change in BMI after 52 weeks of treatment for setmelanotide versus placebo. Key secondary endpoints after 52 weeks are the proportion of patients aged ≥18 years with ≥5% reduction in BMI, proportion of patients aged <18 years with ≥0.2-point reduction in BMI Z score, and mean change in weekly average of the daily “most hunger” score in patients aged ≥12 years. Additional secondary endpoints include proportion of patients achieving ≥2-point reduction in weekly average of the daily maximal hunger score, Symptoms of Hyperphagia total score, additional weight-related parameters, and quality of life outcomes. Exploratory endpoints include change after 52 weeks in physical activity (measured by acDetigraphy), fatigue (via Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue©/Peds FACIT-F© scale), Impacts of Hyperphagia score, caregiver health status (via EuroQol-5-Dimension scale), cardiometabolic parameters, and waist circumference. Safety will be assessed by the frequency and severity of adverse events. Conclusions: This Phase 3 trial designed to assess the efficacy and safety of setmelanotide for weight loss and hunger reduction in patients ≥4 years of age with acquired hypothalamic obesity is planned to initiate in early 2023. Presentation: Friday, June 16, 2023

Abstract Disclosure: M.J. Tansey: Research Investigator; Self; Lumos Pharma, Inc. S.A. Bowden: Research Investigator; Self; Lumos Pharma, Inc. A.N. Dauber: Research Investigator; Self; Lumos Pharma, Inc. B. Wikiera: Research Investigator; Self; Lumos Pharma, Inc. B. Pyrzak: Research Investigator; Self; Lumos Pharma, Inc. A.T. Bossowski: Research Investigator; Self; Lumos Pharma, Inc. E. Petriczko: Research Investigator; Self; Lumos Pharma, Inc. R. Stawerska: Research Investigator; Self; Lumos Pharma, Inc. E. Moszczynska: Research Investigator; Self; Lumos Pharma, Inc. F. Cassorla: Research Investigator; Self; Lumos Pharma, Inc. Speaker; Self; Lumos Pharma, Inc. M.M. Feldt: Research Investigator; Self; Lumos Pharma, Inc. A.J. Lunsford: Research Investigator; Self; Lumos Pharma, Inc. M.E. Gottschalk: Research Investigator; Self; Lumos Pharma, Inc. M. Marin: Research Investigator; Self; Lumos Pharma, Inc. S.N. Nayak: Research Investigator; Self; Lumos Pharma, Inc. S. Bhuvana: Research Investigator; Self; Lumos Pharma, Inc. D.R. Repaske: Research Investigator; Self; Lumos Pharma, Inc. L.A. Soyka: Research Investigator; Self; Lumos Pharma, Inc. J.S. Fuqua: Research Investigator; Self; Lumos Pharma, Inc. O. Escobar: Research Investigator; Self; Lumos Pharma, Inc. D.A. Bowlby: Research Investigator; Self; Lumos Pharma, Inc. P.Y. Fechner: Research Investigator; Self; Lumos Pharma, Inc. E. Wiltshire: Research Investigator; Self; Lumos Pharma, Inc. M. Harris: Research Investigator; Self; Lumos Pharma, Inc. K.A. Wintergerst: Research Investigator; Self; Lumos Pharma, Inc. A.R. Lafferty: Research Investigator; Self; Lumos Pharma, Inc. B.S. Miller: Research Investigator; Self; Lumos Pharma, Inc. P. Simm: Research Investigator; Self; Lumos Pharma, Inc. A. Bruchey: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. C. Smith: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. D.B. Karpf: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. J.C. McKew: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. Background: LUM-201 (ibutamoren), a growth hormone (GH) secretagogue receptor 1a (GHSR1a) agonist, is a potent, long-acting investigational oral GH secretagogue currently studied in three Idiopathic Pediatric GH Deficiency (iPGHD) studies. The LUM-201 predictive enrichment marker (PEM) is used to identify patients diagnosed with iPGHD (peak stimulated GH >3<10 ng/mL) who are likely to respond to LUM-201. PEM positivity is defined as a baseline insulin-like growth factor-1 (IGF-1) level >30 ng/mL and a peak GH of ≥5 ng/mL in response to a single 0.8 mg/kg dose of LUM-201. Objectives: Report the growth response analyzing the combined interim analysis (IA) data from two Phase 2 trials studying LUM-201 at two different doses (1.6 mg/kg/day or 3.2 mg/kg/day). Methods: IA data from both studies were combined and analyzed for calculated annualized height velocity (AHV). Baseline demographics were analyzed for the two combined cohorts. Results: After 6 months of treatment with LUM-201, the calculated AHV (mean ±SD ) was 8.1±1.9 cm/year in the 1.6 mg/kg/day group and 8.0±1.5 cm/year in the 3.2 mg/kg/day group (N=15 in both groups). After 9 months of treatment, the calculated AHV was 7.8±1.7 cm/year in the 1.6 mg/kg/day group and 7.3±1.7 cm/year in the 3.2 mg/kg/day group (N=10 in both groups). After 12 months of treatment, the calculated AHV was 7.8±1.7 cm/year in the 1.6 mg/kg/day group and 7.4 ±1.2 cm/year in the 3.2 mg/kg/day group (N=6 in both groups). LUM-201 was well tolerated; no safety concerns were identified across the dose range in adverse events (AE) data, laboratory values, and ECG values. Conclusions: As the growth velocity was comparable for the two doses of oral LUM-201, this analysis of the combined IA data appears to strongly support 1.6 mg/kg/day as the optimal dose for the Phase 3 trial, as doubling the dose appeared to offer no meaningful improvement in efficacy. Final determination will await final full data set analysis of both studies. Presentation: Saturday, June 17, 2023

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract Disclosure: C.L. Roth: Other; Self; Received research support from Rhythm Pharmaceuticals, Inc. A.H. Shoemaker: Advisory Board Member; Self; Received payments from Rhythm Pharmaceuticals, Inc and Saniona for advisory boards and lectures. Other; Self; Received research support from Rhythm Pharmaceuticals, Inc. M. Gottschalk: Advisory Board Member; Self; Received compensation for consulting and participation on advisory boards from Rhythm Pharmaceuticals, Inc. Other; Self; Received funding for clinical trials from Rhythm Pharmaceuticals, Inc. J. Miller: Other; Self; Received research support from Harmony Biosciences, Rhythm Pharmaceuticals, Inc, Soleno Therapeutics, and Tryp Therapeutics. G. Yuan: Employee; Self; Employee of Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Has company-awarded RSU and options. S. Malhotra: Employee; Self; Employee of Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Stockholder in in Rhythm Pharmaceuticals, Inc. C. Scimia: Employee; Self; Employee of Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Has company-awarded RSU and options. M. Abuzzahab: Advisory Board Member; Self; Received compensation for advisory board participation from Consynance, Endo Pharmaceutical, Pfizer, and Rhythm Pharmaceuticals, Inc. Consulting Fee; Self; Received compensation for consulting from Consynance, Endo Pharmaceutical, Pfizer, and Rhythm Pharmaceuticals, Inc. Speaker; Self; Received compensation for speaking engagements from Consynance, Endo Pharmaceutical, Pfizer, and Rhythm Pharmaceuticals, Inc. Other; Self; Received research support from Ascendis, Levo Pharmaceuticals, Lumos, NovoNordisk, Rhythm Pharmaceuticals, Inc, Saniona, and Soleno. Background: Hypothalamic obesity (HO) is an acquired form of severe obesity characterized by rapid and excessive weight gain resulting from insult to the hypothalamus—primarily caused by tumor invasion, resection, or radiotherapy—that can impair melanocortin-4 receptor (MC4R) pathway signaling. Treatment with setmelanotide, an MC4R agonist, resulted in weight loss and hunger reduction at 16 weeks in a Phase 2 trial of patients with HO. Here, we report changes in age-appropriate weight-related parameters after 6 months of treatment with setmelanotide in patients with HO who entered a long-term extension (LTE) trial. Methods: A Phase 2, multicenter, open-label study (NCT04725240) examined the efficacy and safety of 16-week setmelanotide treatment in patients aged ≥6 to ≤40 years with a clinical diagnosis of HO. Patients who met the primary endpoint of ≥5% body mass index (BMI) reduction from baseline at Week 16 or experienced investigator-determined clinically meaningful benefit and demonstrated adequate safety were eligible to enroll in the LTE trial (NCT03651765). We assessed the proportion of patients who achieved ≥10% BMI reduction as well as changes in age-appropriate weight-related parameters (ie, mean percent change in body weight for adults [aged ≥18 years] and mean change in BMI Z score and percent of the 95th BMI percentile [%BMI95] for children [aged <18 years]) from index trial baseline to Month 6 of setmelanotide treatment. Results: Of 18 patients originally enrolled in the index trial, 14 (77.8%) continued into the LTE and 13 (72.2%) had received ≥6 months of setmelanotide treatment at the time of this analysis. HO was diagnosed in these patients secondary to treatment of craniopharyngioma (n=11), hypothalamic hamartoma (n=1), and juvenile pilocytic astrocytoma (n=1). At Month 6, 11 of 13 patients (84.6% [90% confidence interval, 59.0%–97.2%) achieved ≥10% BMI reduction from index trial baseline; the remaining 2 patients achieved ≥5% reduction from baseline at Month 6. In adults (n=2), the mean (standard deviation [SD]) percent change in body weight from baseline to Month 6 was −16.2% (7.2%). In children (n=11), the mean (SD) change from baseline in BMI Z score was −1.7 (1.1) and in %BMI95 was −34.8 (14.9) percentage points at Month 6. The most frequent adverse events were nausea (n=9 [69.2%]), skin hyperpigmentation (n=5 [38.5%]), and vomiting (n=4 [30.8%]). Four serious adverse events were reported in 2 patients (Clostridium difficile colitis in 1 patient; malaise, septic shock, and influenza in 1 patient) and were determined not related or unlikely related to study drug. Conclusions: In a heterogeneous population of patients with HO secondary to treatment of hypothalamic tumors, 6 months of setmelanotide treatment was associated with sustained meaningful improvements in weight and BMI with no new safety signals. Presentation: Saturday, June 17, 2023

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The endocrine pancreas is one of the most inaccessible organs of the human body. Its autoimmune attack leads to type 1 diabetes (T1D) in a genetically susceptible population and a lifelong need for exogenous insulin replacement. Monitoring disease progression by sampling peripheral blood would provide key insights into T1D immune-mediated mechanisms and potentially change preclinical diagnosis and the evaluation of therapeutic interventions. This effort has been limited to the measurement of circulating anti-islet antibodies, which despite a recognized diagnostic value, remain poorly predictive at the individual level for a fundamentally CD4 T cell-dependent disease. Here, peptide-major histocompatibility complex tetramers were used to profile blood anti-insulin CD4 T cells in mice and humans. While percentages of these were not directly informative, the state of activation of anti-insulin T cells measured by RNA and protein profiling was able to distinguish the absence of autoimmunity versus disease progression. Activated anti-insulin CD4 T cell were detected not only at time of diagnosis but also in patients with established disease and in some at-risk individuals. These results support the concept that antigen-specific CD4 T cells might be used to monitor autoimmunity in real time. This advance can inform our approach to T1D diagnosis and therapeutic interventions in the preclinical phase of anti-islet autoimmunity.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract Disclosure: M.J. Abuzzahab: Advisory Board Member; Self; Pfizer, Inc., Endo Pharmaceuticals, Rhythm Pharmaceuticals, Inc., Consynance. Consulting Fee; Self; Pfizer, Inc., Endo Pharmaceuticals, Consynance, Rhythm Pharmaceuticals, Inc. A. Shoemaker: Advisory Board Member; Self; Rhythm Pharmaceuticals, Saniona. M. Gottschalk: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc. Consulting Fee; Self; Rhythm Pharmaceuticals, Inc. J. Miller: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. G. Yuan: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. S. Malhotra: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. C. Scimia: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. C.L. Roth: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. Background: Hypothalamic obesity (HO) is a severe form of obesity that results from insult to the hypothalamus, primarily from tumors, tumor resections, and radiotherapy treatment, which can impair melanocortin-4 receptor (MC4R) pathway signaling. Treatment with setmelanotide, an MC4R agonist, resulted in weight loss and hunger reduction in a Phase 2 trial of patients with HO. This analysis evaluated the impact of 16 weeks of setmelanotide on metabolic parameters and vital signs in patients with HO. Methods: A Phase 2 open-label trial of setmelanotide enrolled patients aged ≥6 to ≤40 years with obesity resulting from hypothalamic injury who completed tumor-related treatment ≥6 months before enrollment (NCT04725240). The primary endpoint was the proportion of patients with ≥5% reduction in baseline body mass index (BMI) after 16 weeks of setmelanotide. Exploratory endpoints of change from baseline in waist circumference and metabolic parameters, including fasting glucose and glycated hemoglobin, were evaluated. Vital signs, including heart rate and blood pressure, were also assessed. Descriptive statistics including changes at Week 16 from baseline are reported. Results: Eighteen patients were included in the study. At Week 16, most patients met the primary endpoint (88.9% [n/N=16/18]; P<0.0001), and 13 of 18 patients who completed treatment had ≥10% BMI reduction (mean [standard deviation (SD)] percent change, −14.5% [9.5%]). Across all patients, body weight was reduced by a mean (SD) of 12.6% (9.1%), and change in BMI Z score in patients aged ≥6 to <18 years was −1.3 (1.0). Overall, waist circumference was reduced by a mean (SD) of 12.0 (5.8) cm, which was a 10.4% (5.2%) reduction. Weight loss was predominately due to reduction in total fat mass rather than loss of lean mass. Most mean metabolic and vital sign values were within normal ranges at baseline, and given the short duration of the study, no changes in metabolic parameters were noted. Vital signs continued to remain normal during the 16-week study duration. Treatment-related adverse events occurred in all patients. The most frequent adverse events included nausea (61.1%; n=11), vomiting (33.3%; n=6), skin hyperpigmentation (33.3%; n=6), and diarrhea (22.2%; n=4). Conclusions: In a heterogeneous population of patients with HO secondary to treatment of hypothalamic tumors, setmelanotide led to weight loss and reduction in BMI and a favorable change in body composition. Efficacy and safety of setmelanotide will continue to be evaluated in a larger Phase 3 clinical trial. Presentation: Friday, June 16, 2023

Abstract Background: In the IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, Type 1 diabetes mellitus is the most common endocrine complication and usually occurs with a variable presentation from immediately at birth to within the first few months of life. Clinical case: A four-month-old male presented for evaluation of failure to thrive, eczema, and diarrhea. In the ED, his glucose value was 246 mg/dL with beta-hydroxybutyrate of 0.29 mmol/L (0.00-0.30). Within eight hours and without insulin, he became hypoglycemic and required dextrose-containing fluids to maintain euglycemia; he was quickly made NPO and started on TPN due to excessive stool output. For nearly two weeks he required no insulin while receiving 84g of dextrose per day (21 g/kg/day) in TPN. He developed bloody stools on the day that he started receiving Tacrolimus and IVIG and required transfer to the ICU, and an insulin need of 1 unit/kg/day developed with this worsening of his systemic illness. After the bloody stools resolved, immunosuppression with Rituximab was initiated. Once bowel function improved, Pedialyte and formula were slowly reintroduced and for three weeks his insulin requirement varied from 0.2-0.4 units/kg/day. In his seventh week of hospitalization his insulin was discontinued due to hypoglycemia, and at the time of discharge he had been without insulin for ten days on ad lib formula feeding. Hemoglobin A1c on admission was 10.2%, and repeat was 10.3%. A fructosamine level was obtained to evaluate the discrepancy between the initial HgbA1c and being euglycemic. It was 269 umol/L (190-270), equivalent to an approximate HgbA1c of 6.5%, suggesting that hyperglycemia resulting in an elevated HgbA1c occurred early in his life and had improved in the days to weeks prior to admission. Further testing revealed an elevated GAD-65 antibody of >250 IU/mL (<5) but normal ICA 512 and insulin autoantibody. His clinical picture was consistent with IPEX syndrome, confirmed with rapid whole genome sequencing showed a pathogenic hemizygous c.1010G>A p.Arg337Gln variant in the FOXP3 gene. A HgbA1c performed prior to discharge, eight weeks after the initial, was 6.6%. This spontaneous resolution of hyperglycemia in IPEX, with insulin needs developing only when he had worsening systemic illness as demonstrated by bloody stools, has yet to be described. Conclusion: Hyperglycemia fluctuated in the first few months of life in a patient with IPEX syndrome, likely related to severity of systemic illness and control of enteropathy.