Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial.

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 3·0 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. FINDINGS: 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 15·0 years (SD 5·3) and a mean BMI of 38·0 kg/m2 (SD 6·5). 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<0·0001). 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<0·0001), comprising a reduction in BMI Z score of at least 0·2 points for patients younger than 18 years (92%, 68-100%; p<0·0001) and reduction in bodyweight of at least 5% for patients aged 18 years or older (80%, 34-99%; p<0·0001). 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. FUNDING: Rhythm Pharmaceuticals.

Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study.

OBJECTIVE: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). METHODS: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. RESULTS: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). CONCLUSIONS: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled. OBJECTIVE: The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. METHODS: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. RESULTS: DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). CONCLUSION: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.

Approach to the Patient With Hypothalamic Obesity.

Hypothalamic obesity (HO) is defined as abnormal weight gain due to physical destruction of the hypothalamus. Suprasellar tumors, most commonly craniopharyngiomas, are a classic cause of HO. HO often goes unnoticed initially as patients, families, and medical teams are focused on oncologic treatments and management of panhypopituitarism. HO is characterized by rapid weight gain in the first year after hypothalamic destruction followed by refractory obesity due to an energy imbalance of decreased energy expenditure without decreased food intake. Currently available pharmacotherapies are less effective in HO than in common obesity. While not a cure, dietary interventions, pharmacotherapy, and bariatric surgery can mitigate the effects of HO. Early recognition of HO is necessary to give an opportunity to intervene before substantial weight gain occurs. Our goal for this article is to review the pathophysiology of HO and to discuss available treatment options and future directions for prevention and treatment.

The Efficacy, Safety, and Pharmacology of a Ghrelin O-Acyltransferase Inhibitor for the Treatment of Prader-Willi Syndrome.

CONTEXT: Acylated ghrelin (AG) stimulates appetite and is elevated compared to its unacylated (UAG) counterpart in Prader-Willi syndrome (PWS). GLWL-01 is a selective, reversible inhibitor of ghrelin O-acyltransferase (GOAT), the enzyme that converts UAG into AG. OBJECTIVE: This work aimed to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients. METHODS: A double-blind, placebo-controlled, phase 2 crossover study was conducted with 2 active treatment periods of 28 days in 19 patients (aged 16-65 years; body mass index (BMI) ≥ 28) with genetically confirmed PWS. The study took place in 7 hospital-based study centers in the United States and Canada. Patients received placebo or GLWL-01 (450 mg twice daily) orally after lead-in placebo and washout periods. The Hyperphagia Questionnaire for Clinical Trials and Caregiver Global Impression of Change were used to measure reductions in hyperphagia. Plasma concentrations of AG and UAG were evaluated as correlates. RESULTS: Treatment resulted in statistically significant differences compared to placebo in plasma AG (P = .0002), UAG (P = .0488), and AG/UAG (P = .0003). GLWL-01 did not statistically significantly reduce hyperphagia-related behavior or bring about changes in global clinical end points, as assessed by caregivers. Anthropometric and clinical parameters correlated with obesity did not statistically significantly change in response to treatment. Less than half of patients reported a treatment-emergent adverse event (TEAE). No deaths, serious adverse events, or severe TEAEs were reported. CONCLUSION: GLWL-01 is safe and well tolerated. Pharmacological parameters confirmed the inhibition of GOAT following administration of GLWL-01. Patients' eating behaviors, BMI, blood glucose, and total cholesterol, among other similar measures, were not modified.

Energy balance in hypothalamic obesity in response to treatment with a once-weekly GLP-1 receptor agonist.

BACKGROUND/OBJECTIVES: Hypothalamic obesity (HO) frequently occurs following suprasellar tumors from a combination of decreased energy expenditure and increased energy intake. Glucagon-like peptide-1 receptor agonist (GLP1RA) therapy is associated with increased satiety and energy expenditure. We hypothesized GLP1RA therapy in patients with HO would cause both lower energy intake and increased energy expenditure. SUBJECTS/METHODS: Forty-two patients aged 10-26 years (median 16 years) with HO with suprasellar tumors were randomized to GLP1RA (exenatide extended release once-weekly, ExQW, n = 23) or placebo (n = 19). Thirty seven (81%) patients completed the 36-week double-blind placebo-controlled trial. Total energy expenditure (TEE) was measured with doubly labeled water, physical activity was assessed with actigraphy, and intake was estimated with ad libitum buffet meal. Results are presented as adjusted mean between-group difference. RESULTS: As compared with treatment with placebo, treatment with ExQW was associated with decreased energy intake during a buffet meal (-1800 kJ (-430 kcal), 95% CI -3 184 to -418 kJ, p = 0.02). There were no significant differences in physical activity between groups. ExQW (vs. placebo) treatment was associated with a decrease in TEE (-695 kJ/day (-166 kcal/day), 95% CI -1 130 to -264 kJ/day, p < 0.01, adjusted for baseline TEE). The treatment effect was still significant after further adjustment for change in body composition (-372 kJ/day (-89 kcal/day), 95% CI -699 to -42 kJ/day, p = 0.04) or change in leptin (-695 kJ/day (-166 kcal/day), 95% CI -1 130 to -264 kJ/day, p < 0.01). This decrease in TEE occurred despite an increase in lean mass and fat mass (1.7 vs. 1.3 kg lean mass, p = 0.88 and 1.5 vs. 4.6 kg fat mass, p = 0.04, ExQW vs. placebo). CONCLUSIONS: Treatment with a GLP1RA was associated with a decrease in food intake but also a decrease in TEE that was disproportionate to change in body composition.

A phase 3 randomized clinical trial using a once-weekly glucagon-like peptide-1 receptor agonist in adolescents and young adults with hypothalamic obesity.

AIM: To evaluate the efficacy, safety and tolerability of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in patients with hypothalamic obesity (HO). MATERIALS AND METHODS: A two-arm, randomized, multicentre, double-blind, placebo-controlled trial was conducted in 10- to 25-year-olds with hypothalamic injury following intracranial tumour and HO. Participants were randomized to once-weekly subcutaneous injections of a GLP-1 RA exenatide 2 mg (ExQW) or placebo for 36 weeks. The primary efficacy endpoint was 36-week % change in body mass index (BMI). Secondary outcomes included change in body composition (by dual energy x-ray absorptiometry). RESULTS: Forty-two participants were randomized to ExQW (n = 23) or placebo (n = 19). Participants were 5 ± 2 years (mean ± SD) postdiagnosis and development of HO (BMI 37.3 ± 7.1 kg/m2 ). In intention-to-treat analysis, the effect of 36-week ExQW vs. placebo on % Δ BMI was not significant (estimated treatment difference -1.7 ± 1.8%, 95% CI -4.1 to 0.6%, P = .40); however, total body fat mass was reduced (estimated treatment difference -3.1 ± 1.4 kg, 95% CI -5.7 to -0.4 kg, P = .02). There was a significant reduction in waist circumference (estimated effect of treatment -3.5 [95% CI -5.5 to -1.6] cm, P = .004). All patients treated with placebo increased % of adipose tissue, while 50% treated with ExQW had reductions (P < .001). Mean HbA1c, glucose tolerance and serum lipids did not change significantly with therapy. ExQW was well tolerated. The most frequent adverse events were transient gastrointestinal disturbances (ExQW vs. placebo: nausea 6/23 vs. 3/18, vomiting 4/23 vs. 4/18 and diarrhoea 7/23 vs. 3/18). CONCLUSIONS: GLP-1 RAs are a promising and safe treatment to improve or stabilize HO in children and young adults.

Trends in pediatric obesity management, a survey from the Pediatric Endocrine Society Obesity Committee.

Background In the United States, 18.5% of children are obese. Dietary and lifestyle modifications are key, but often ineffective. There are limited approved pediatric pharmacotherapies. The objective of this study was to evaluate current treatment practices for pediatric obesity among members of the Pediatric Endocrine Society (PES, n = 1300) and the Pediatric Obesity Weight Evaluation Registry (POWER, n = 42) consortium. Methods A 10-question online survey on treatment of children with obesity in clinical practice was conducted. Results The response rates were 19% for PES and 20% for POWER members. The majority were female (65%) and board certified in pediatric endocrinology (81%). Most practitioners saw 5-10 patients with obesity/week and 19% prescribed weight-loss medications. POWER participants were more likely to prescribe weight-loss medications than PES participants (46% vs. 18%, p = 0.02). Metformin was the most commonly prescribed medication. Response to medication was poor. Use of dietary non-pharmacological treatment options was uncommon. Over half of the respondents (56%) referred patients for bariatric surgery and 53% had local access to pediatric bariatric surgery. Conclusions Metformin was the most common drug prescribed among respondents, but successful weight-loss responses were uncommon. Among practitioners who are using pharmacological interventions, therapeutic strategies vary widely. Targeted research in pharmacologic and surgical treatment for pediatric obesity is urgently needed.

Hypothalamic Obesity: Prologue and Promise.

Hypothalamic obesity (HO) frequently occurs following damage to the medial hypothalamic region, encompassing the arcuate nucleus, the paraventricular nucleus, the ventromedial nucleus, the dorsomedial nucleus, and the dorsal hypothalamic area, which are critically involved in the regulation of satiety and energy balance through neural and humoral connections. HO is most commonly described in the context of craniopharyngioma and its treatment, but it can also occur following other suprasellar tumors, radiation, trauma, or a surgical insult to the hypothalamus. A constellation of loss of satiety and a reduction of the metabolic rate, thermogenesis, and physical activity as well as increased vagal tone and hyperinsulinism with insulin and leptin resistance results in rapid weight gain due to a decreased energy expenditure and increased energy storage in adipose cells. To date, no viable long-term solution for HO has been found, due either to the requirement of intact hypothalamic pathways or to significant side effects. Newer therapeutic modalities focused on the unique pathophysiology of this condition offer potential for successful treatment. In this review, we describe the etiology of HO as well as past/current treatment approaches in the categories of hyperinsulinism, surgical approaches, and targeting energy expenditure/anorectic drugs. We conclude by providing an overview of the clinical trials currently underway.

Glucose Homeostasis and Energy Balance in Children With Pseudohypoparathyroidism.

Context: Pseudohypoparathyroidism (PHP) is a rare genetic disorder characterized by early-onset obesity and multihormone resistance. To treat abnormal weight gain and prevent complications such as diabetes, we must understand energy balance and glucose homeostasis in PHP types 1A and 1B. Objective: The aim of this study was to evaluate food intake, energy expenditure, and glucose homeostasis in children with PHP. Design: Assessments included resting energy expenditure (REE), physical activity, food intake, sucrose preference, questionnaires, endocrine status, and auxological status. All patients underwent an oral glucose tolerance test (OGTT). Setting: Vanderbilt University Medical Center. Patients: We assessed 16 children with PHP1A, three with PHP1B, and 15 healthy controls. Main Outcome Measures: Food intake during an ad lib buffet meal and glucose at five time points during OGTT. Results: PHP1A and control groups were well matched. Participants with PHP1A had significantly lower REE without concomitant change in food intake or physical activity. At baseline, participants with PHP1A had significantly lower fasting glucose and insulin resistance. During OGTT, participants with PHP1A had significantly delayed peak glucose and a slower rate of glucose decline despite similar oral glucose insulin sensitivity. Participants with PHP1A had 0.46% lower HbA1c levels than controls from a clinic database after adjustment for OGTT 2-hour glucose. The PHP1B group was similar to the PHP1A group. Conclusions: In contrast to other monogenic obesity syndromes, our results support reduced energy expenditure, not severe hyperphagia, as the primary cause of abnormal weight gain in PHP. Patients with PHP are at high risk for dysglycemia without reduced insulin sensitivity.

Obstructive Sleep Apnea and Otolaryngologic Manifestations in Children with Pseudohypoparathyroidism.

BACKGROUND/AIMS: Pseudohypoparathyroidism (PHP) is a rare, genetic disorder. Patients with PHP may have increased prevalence of obstructive sleep apnea (OSA) but this has not been prospectively studied. METHODS: We enrolled children aged 6-18 years with PHP and matched controls. Evaluation included physical examination, medical history, and polysomnography. RESULTS: Fifteen children with PHP type 1A (PHP1A) and 15 controls completed the study. Both groups were obese (BMI 32.2 ± 8.7 vs. 31.7± 6.5). The majority of PHP1A patients required tympanostomy tubes (86.7%) and adenotonsillectomy (73.3%). The primary outcome, i.e., the obstructive disturbance index, was significantly higher in PHP1A children versus controls (1.8 ± 2.3 vs. 0.6 ± 0.5, p = 0.045). Children with PHP1A were more likely to have OSA compared with controls (60.0 vs. 13.3%, p = 0.008). Three siblings with PHP type 1B (PHP1B) were also studied (BMI 25.9 ± 9.0). None had a history of adenotonsillectomy, one had tympanostomy tubes. The obstructive disturbance index (2.0 ± 2.3) was similar to that of children with PHP1A. Two (66.7%) PHP1B participants had OSA. CONCLUSION: Children with PHP1A are at an increased risk for OSA compared with similarly obese peers. They also have higher rates of otitis media and adenotonsillar hypertrophy. Screening for OSA should be considered in all patients with PHP1A and possibly PHP1B though more research is needed.

Strengthening brittle bones.

Decreased WNT1 signaling weakens bones but is partially reversed by blocking the WNT1 inhibitory regulator sclerostin.

A 52-week pilot study of the effects of exenatide on body weight in patients with hypothalamic obesity.

OBJECTIVE: Hypothalamic obesity (HO) is a common complication of hypothalamic tumors, and effective therapies are lacking. The objective of this pilot study was to investigate changes in body weight before and during treatment with exenatide. METHODS: This was a prospective, open-label, 52-week pilot study of exenatide (10 mcg b.i.d.) in adults with HO. Ten patients enrolled, and eight completed the study. Study measures included indirect calorimetry, body composition, buffet meals, diet recall, actigraphy, and hormone assays. RESULTS: Participants had obesity with a baseline weight of 137.2 ± 37.6 kg. Exenatide therapy was well tolerated. Change in weight with exenatide therapy was not significant (-1.4 ± 4.3 kg [95% CI -4.9 to 2.2], P = 0.40), but six out of eight completers lost weight (-6.2 to -0.2 kg). Participants reported significantly lower intake on food recall during treatment compared with baseline (7837.8 ± 2796.6 vs. 6258.4 ± 1970.7 kJ [95% CI -2915.8 to -242.6], P = 0.027), but there was no change in intake during buffet meals. CONCLUSIONS: Significant weight loss was not observed in patients with HO treated with exenatide, but 75% of completers had stable or decreasing weight. Further studies are needed to evaluate weight loss efficacy in patients with HO.

Treatment with glucagon-like Peptide-1 agonist exendin-4 in a patient with hypothalamic obesity secondary to intracranial tumor.

BACKGROUND/AIMS: Patients with hypothalamic tumors frequently experience severe obesity, and its treatment with diet, exercise, and/or pharmacologic treatment has had limited effect. Glucagon-like peptide-1 agonist exenatide (exendin-4), used for treatment of type 2 diabetes, causes persistent weight loss via signaling in the brainstem. METHODS: We report the case of a 17-year-old patient with obesity resulting from a hypothalamic germ cell tumor. He was treated by chemoradiotherapy and exenatide at a dose of 5 µg subcutaneously twice daily. RESULTS: Exenatide resulted in a 29-kg weight loss (BMI reduction from 37.1 to 29.1) after 2.5 years of treatment; significant weight gain occurred shortly after exenatide was discontinued. CONCLUSION: Exenatide resulted in considerable reduction of body weight in a patient with severe hypothalamic obesity. This novel observation requires follow-up clinical studies for establishing the effects of exenatide in patients with disrupted hypothalamic energy regulatory pathways.

Neuroendocrine carcinoma in an adolescent with hypercortisolemia.

We present a 16-year-old boy with weakness, hypercortisolemia, and markedly elevated adrenocorticotropic hormone. Computed tomographic imaging revealed hepatic lesions and a calcified pancreatic mass. Biopsy of the hepatic lesions revealed moderately differentiated neuroendocrine carcinoma. The primary tumor could not be determined. The patient received neoadjuvant chemotherapy with carboplatin and etoposide followed by therapeutic bilateral adrenalectomy and tumor debulking. Despite significant clinical improvement, restaging revealed progressive hepatic disease. The patient died 9 months after diagnosis. Autopsy revealed disseminated neuroendocrine carcinoma. The rarity of this tumor compels a cooperative investigational model involving pediatric and adult oncologists.

Increased prevalence of carpal tunnel syndrome in albright hereditary osteodystrophy.

CONTEXT: Albright hereditary osteodystrophy (AHO) is a rare genetic disorder characterized by phenotypic abnormalities including brachydactyly/brachymetacarpia, short stature, and sc ossifications. Carpal tunnel syndrome (CTS) is a chief complaint in many patients with AHO. OBJECTIVE: The objective of the study was to investigate the prevalence of CTS in patients with AHO. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at the Clinical Research Center (Institute of Clinical and Translational Medicine), Johns Hopkins University School of Medicine and Albright Clinic, Kennedy Krieger Institute. PARTICIPANTS: Thirty-three subjects with a diagnosis of AHO participated in the study. MAIN OUTCOME MEASURES: We assessed for the presence and location of hand tingling, numbness, pain, weakness, flick sign, difficulty with fine motor skills, severe hand or nail biting, and nocturnal symptoms in the setting of normocalcemia and a euthyroid state. Patients were considered to have CTS if they were positive for three of these symptoms. All subjects were analyzed for mutations in the GNAS gene. RESULTS: Twenty-two subjects (67%) had a clinical diagnosis of CTS (95% confidence interval 0.48, 0.82). Twenty-eight of 33 subjects were confirmed to have mutations in GNAS, of whom 68% had CTS (95% confidence interval 0.48, 0.84). There were 14 children in this study; 36% had a clinical diagnosis of CTS. Body mass index, brachydactyly/brachymetacarpia, prior GH treatment, and specific GNAS mutations were not associated with CTS. CONCLUSIONS: We report a high prevalence of CTS in both adults and children with AHO. The diagnosis of CTS should be considered when evaluating a patient with AHO because the intervention for CTS could improve overall function and quality of life in these patients.