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Background: Injectable somatostatin receptor ligands (iSRLs) have been a mainstay in acromegaly treatment. Oral octreotide capsules (OOC; MYCAPSSA®) were recently approved in the United States. Results from the placebo-controlled CHIASMA OPTIMAL and open-label CH-ACM-01 studies showed an OOC safety profile consistent with that of iSRLs with no new or unexpected safety signals. Results of the MPOWERED trial have enabled a comparison of OOC safety and efficacy with iSRLs. Methods: To enter MPOWERED, patients must have the following: acromegaly diagnosis, biochemical control of acromegaly (insulin-like growth factor I Results: In the RCT, incidence of treatment-emergent adverse events (TEAEs) was similar between groups; 39 patients (70.9%) in the OOC group and 26 (70.3%) in the iSRL group had ≥1 TEAE. 19 patients (34.5%) in the OOC and 15 (40.5%) in the iSRL group had treatment-related TEAEs. Occurrence was similar for serious AEs (OOC, 5.5%; iSRL, 8.1%) as well as TEAEs classified as severe (OOC, 9.1%; iSRL, 10.8%). One patient in the OOC group discontinued due to a TEAE. The most common gastrointestinal TEAEs were flatulence (OOC, 25.5%; iSRL, 21.6%), nausea (OOC, 20.0%; iSRL, 8.1%), diarrhea (OOC, 10.9%; iSRL, 13.5%), abdominal pain (OOC, 9.1%; iSRL, 8.1%), and constipation (OOC, 5.5%; iSRL, 13.5%). AEs of interest were infrequent, including cholelithiasis (OOC, n=0; iSRL, n=1 [2.7%]) and secondary hypothyroidism (OOC, n=1 [1.8%]; iSRL, n=0). In the iSRL group, 32.4% of patients reported injection site reactions (ISRs) during the RCT, and 47% of patients reported ISRs as part of the Acromegaly Treatment Satisfaction Questionnaire, a newly validated patient-reported outcome tool.1 Conclusion: Safety results from MPOWERED align with prior trials, showing that the OOC safety profile is consistent with that of iSRLs as well as the acromegaly disease burden. No new or unexpected safety signals were identified during the trial. Safety results were mostly similar between OOC and iSRLs, although patients in the OOC group did not experience any ISRs. 1Fleseriu M, et al. Pituitary. 2020 Aug;23(4):347-358.

Introduction: During the 22-week core LINC 2 study, the oral 11β-hydroxylase inhibitor osilodrostat normalized mean urinary free cortisol (mUFC) in 79% (15/19) of patients with Cushing’s disease. This report describes long-term LINC 2 efficacy and safety results following an optional extension. Methods: Patients receiving clinical benefit at week 22 could enter the extension (that ran until Oct 22, 2019), continuing the same osilodrostat dose; dose adjustments were permitted based on efficacy and safety. Response rate (mUFC ≤ULN [controlled] or mUFC >ULN but ≥50% decrease from baseline [BL; partially controlled]) was assessed over time. Efficacy/safety were assessed for all patients from core BL until study end. Results: Of 19 enrolled patients (female:male 14:5; mean [SD] age 36.8 years [8.4]), 16 entered the optional extension and 8 of them remained on treatment until study end. Median (range) osilodrostat exposure was 282 weeks (2-351). Mean mUFC decreased from BL (9.9 x ULN) to ≤ULN by week 4 and remained stable throughout the study. All 19 patients achieved mUFC ≤ULN at least once during the study. At each assessment up to month 70 of the extension phase, 50-88% of ongoing patients were controlled, and up to 18% were partially controlled. Mean percentage change in clinical signs from BL (mean [SD]) to last assessment were: fasting plasma glucose, -10.8% (22.1) (from BL: 105.6 mg/dL [49.2]); HbA1c, -2.1% (9.0) (from BL: 5.7% [0.7]); systolic BP, -3.3% (12.6) (from BL: 132.6 mmHg [11.6]); diastolic BP, -2.0% (10.4) (from BL: 85.0 mmHg [6.5]); BMI, -5.9% (8.8) (from BL: 30.7 kg/m2 [7.0]). Overall, 9 patients discontinued treatment (n=2 core and n=7 extension), mostly because of AEs or no longer requiring treatment (n=3 each). The most common AEs during the entire treatment period were nausea (n=10), adrenal insufficiency, and headache (both n=9). AEs related to hypocortisolism and adrenal hormone precursor accumulation occurred in 11 (mostly adrenal insufficiency, n=9) and 12 patients (mostly hypertension, n=4), respectively; most were grade 1/2 and managed with dose adjustment/interruption and/or concomitant medication. Mean (SD) plasma ACTH increased from 1.8 x ULN (0.9) at BL to 7.1 x ULN (12.3) at week 22 and 6.9 x ULN (12.6) at last assessment. Mean (SD) 11-deoxycortisol increased from 1.2 x ULN (1.3) at BL to 13.6 x ULN (12.2) at week 22 and 3.6 x ULN (4.2) at last assessment. In females, mean (SD) testosterone increased from 0.8 x ULN (0.4) at BL to 2.4 x ULN (2.1) at week 22 and 1.0 x ULN (0.9) at last assessment. Two patients, both female, reported an AE of hirsutism. Conclusions: Rapid reductions in mUFC were sustained for up to 6 years of osilodrostat treatment and were accompanied by improvements in clinical signs of hypercortisolism. Osilodrostat was well tolerated, with no new safety signals during long-term treatment.

Background: Improved patient-reported outcomes (PROs) are increasingly becoming a key treatment objective in acromegaly. Validated PROs were used to assess disease and treatment burden in the MPOWERED phase 3 trial in acromegaly, which also assessed safety and efficacy of oral octreotide capsules (OOC; MYCAPSSA®) compared to injectable SRLs (iSRLs). Methods: Eligible patients had acromegaly diagnosis, biochemical control of acromegaly (insulin-like growth factor I Results: Of 146 enrolled patients, 92 entered RCT (OOC, N=55; iSRLs, N=37). Acro-TSQ scores at the end of Run-in (26 weeks’ OOC treatment) were compared to baseline (iSRLs). In the 92 patients randomized, 3 of 5 Acro-TSQ domains (emotional reaction, treatment convenience, and treatment satisfaction) showed significant improvement at end of Run-in compared to baseline. Injection site interference was not assessed as no injection site reactions were observed with OOC. Other domains showed a nonstatistically significant pattern of improvement at end of Run-in when compared to baseline. Patients randomized to iSRLs in the RCT after receiving OOC in the Run-in (N=37) reported more anxiety (RCT end, 53%; Run-in end, 29%) and frustration (RCT end, 45%; Run-in end, 34%) with iSRLs compared to OOC. Overall treatment satisfaction was higher while receiving OOC (Run-in end, 92%; after receiving iSRLs in RCT, 75%). Breakthrough symptoms were reported more frequently with iSRLs (31%) than OOC (15%) at the end of RCT. Conclusion: Higher patient satisfaction, convenience and emotional well-being, and improved symptom control based on the newly validated Acro-TSQ PRO reporting tool were observed with OOC compared to iSRLs in patients enrolled in the MPOWERED trial. 1Fleseriu M, et al. Pituitary. 2020 Aug;23(4):347-358.

Background: Our registry study is designed to create a unified database of pituitary disease patients in Latvia. Methods: We collected 3 yrs data from medical records with pituitary diseases from one clinical university hospital and 4 outpatients clinics. Prospective cohort analysis was performed based on demographic data, MRI, laboratory data, data on medications and regimens used to treat pituitary diseases, information on co-morbidities and concomitant medications used in 355 patients with various pituitary diseases: prolactinomas, clinically nonfunctional adenomas (CNFA), acromegalies, empty sella syndrome, Cushing’s disease (CD), Ratke’s pocket cysts, meningiomas, craniopharyngoma, pituitary aplasia and hypoplasia, TSH-omas, germinoma, glioma, chondrosarcoma, pericytoma. Results: From July 2016 to July 2019, 355 people (71.7% women) with pituitary diseases were registered. The mean age in the cohort was 43.4 yrs (range 18–83 yrs). Prolactinomas were the most common adenomas (40.8%), followed by CNFA (28.5%), acromegaly (16.1%) and empty sella syndrome (5.1%), CD (2.3%), Ratchet pocket cysts (2.3%), meningiomas (1.4%), craniopharyngiomas (1.1%), pituitary aplasia and hypoplasia (0.8%), TSH-omas (0.6%), germinoma (0.3%), glioma (0.3%), chondrosarcoma (0.3%), pericitoma (0.3%). Female dominance was observed in patients with prolactinoma and CNFA, ​​empty sella syndrome, Ratke’s pocket cysts, CD, meningiomas, TSH-omas. Patients in the cohort most often received drug therapy with any type of medication alone (octreotide LAR, lanreotide, bromocriptine, cabergoline, pegvisomant) in 50.5% of cases; various types of combination therapy in 13% of cases. The majority of patients (81.7%) were treated with 1or more medication for co-morbidity. Thyroid disease was slightly more common than cardiovascular disease: 86.1% vs. 81.3%. In 10.1% of the cohort, cancer of various localities was detected. Both types of diabetes or other disorders of carbohydrate metabolism were found in 36.3% of cases. Conclusion: Based on the study of the pituitary disease register in Latvia, a unified database of pituitary disease patients has been created, which allows analyzing the population characteristics of the pituitary diseases, the applied treatment schemes for the treatment of pituitary diseases; types of neurosurgery, medication and radiation therapy. A state register may be set up in the future.

Background: Oral octreotide capsules (OOC; MYCAPSSA®) are approved in the US for individuals with acromegaly who responded to and tolerated treatment with injectable somatostatin receptor ligands (iSRLs). Add-on cabergoline therapy has shown effectiveness in patients previously inadequately controlled with iSRLS.1 The phase 3 MPOWERED trial assessed maintenance of response with OOC compared to iSRLs. Patients receiving OOC and ineligible for randomized controlled treatment (RCT) phase were eligible for a sub-study evaluating combination therapy with cabergoline, a dopamine agonist. Methods: Patients who fail to respond to 80 mg/d OOC for ≥2 weeks during the 26-week Run-in phase, or ineligible to enter the RCT on 80 mg/d OOC, due to inadequate biochemical control (insulin-like growth factor I [IGF-I] ≥1.3 × upper limit of normal [ULN] to Results: Of 146 patients enrolled in MPOWERED, 14 entered the combination sub-study, 9 having IGF-I ≥1.3 × ULN at sub-study start. Final cabergoline doses were 1 (n=5), 2 (n=3), 3 (n=1), and 3.5 mg (n=5) with 25.4-week (SD, 14.1) mean treatment duration. Week 36 IGF-I improved in most patients (n=12; 85.7%). Of 9 patients with IGF-I ≥1.3 × ULN at sub-study start, 5 (55.6%; 95% CI, 21.2%-86.3%) exhibited IGF-I decreased to predefined responder range ( Conclusion: We have shown for the first time the benefit of an all-oral combination treatment for acromegaly and avoidance of injection-related burdens. Addition of cabergoline to OOC yielded biochemical control improvement (IGF-I reduction) in patients inadequately controlled with OOC monotherapy. As both combination and OOC monotherapy safety profiles were similar, adjunctive cabergoline may be helpful in patients with acromegaly who do not achieve adequate biochemical control on OOC alone. 1Giustina A, et al. Nat Rev Endocrinol. 2014;10(4):243-248.

Background: Patients with acromegaly may have high symptom burden. The phase 3 MPOWERED trial assessed control of acromegaly by oral octreotide capsules (OOC; MYCAPSSA®) in comparison to injectable somatostatin receptor ligands (iSRLs) in patients responding to both OOC and iSRLs. iSRLs have been first-line medical treatment for patients with acromegaly for decades. OOC are newly approved in the US for patients previously controlled on iSRLs. Methods: Eligibility criteria for MPOWERED included acromegaly diagnosis, biochemical control of acromegaly (insulin-like growth factor I Results: At beginning of Run-in, average AIS score of 92 randomized patients was 4.52, representative of symptoms experienced while previously receiving iSRLs. After 26 weeks’ OOC treatment at end of Run-in, average AIS score was significantly reduced to 3.46 (P Conclusion: Results from MPOWERED show that patients receiving OOC had significant improvement in number and severity of acromegaly symptoms after switching from iSRLs. These findings validate previous results from a phase 3 study of OOC in acromegaly in which patients switching to OOC from iSRLs showed significant reduction in joint pain, extremity swelling, and fatigue.1 1Melmed S, et al. JCEM. 2015;100(4):1699-1708.

Introduction: First generation somatostatin analogs (SSAs) are the treatment of choice in persistent acromegaly after transsphenoidal surgery. However, they are effective in 25% to 45 % of patients and a second generation SSA - pasireotide LAR may be a more effective alternative. Aim Our aim was to evaluate the impact of 1-year treatment with pasireotide LAR on disease control and on glucose metabolism in patients with acromegaly after debulking surgery resistant to first-generation SSAs. Material and methods In this single-center prospective study 29 consecutive patients with resistant acromegaly were treated with pasireotide LAR. The initial drug dose was 40 mg i.m. every 28 days. If patient did not achieve biochemical control (GH

Patients with acromegaly not cured by surgery are often initially treated with injected peptide long-acting somatostatin receptor ligands (SRLs). Non-peptide small molecules can also activate the somatostatin receptor and do so with a high degree of precision for the target therapeutic receptor subtype. Paltusotine (formerly {"type":"entrez-protein","attrs":{"text":"CRN00808","term_id":"1048626668","term_text":"CRN00808"}}CRN00808) is a small molecule somatostatin type 2 (SST2) receptor agonist with high oral bioavailability (70%) and pharmacokinetic profile suitable for once daily dosing. In healthy volunteers, paltusotine has been shown to lower growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. We hypothesized that patients with acromegaly could switch from injected SRLs to once daily oral paltusotine while maintaining baseline IGF-1 levels. ACROBAT Edge ({"type":"clinical-trial","attrs":{"text":"NCT03789656","term_id":"NCT03789656"}}NCT03789656) was a single-arm study designed to evaluate the safety and efficacy of switching from injected SRLs to paltusotine in patients with acromegaly. The primary analysis population consisted of those who had not achieved normal IGF-1 levels despite stable therapy with long-acting octreotide or lanreotide. Eligible patients received their last injection of SRL 4 weeks prior to switching to once daily oral paltusotine monotherapy for a 13-week treatment period. The starting dose of 10 mg per day was uptitrated in 10 mg increments at specified study visits to a maximal dose of 40 mg per day based on protocol specified study drug toleration and IGF-1 criteria. The primary endpoint was change in IGF-1 from baseline to the completion of the 13-week treatment period. Statistical testing was based on non-parametric Wilcoxon Sign Rank test of whether the median change is different from zero. In addition, the rise in IGF-1 during a 4-week washout period was used to provide supportive evidence of efficacy. Twenty-five patients were enrolled in the primary analysis group, three patients discontinued from the study for non-study drug related reasons, two during the treatment period and one during the washout period after completing treatment. The primary endpoint was achieved as paltusotine treatment resulted in no significant change in IGF-1 levels at week 13 compared to baseline [change in IGF-1 =-0.034 (-0.107, 0.107), median (IQR), p>0.6]. Of the 23 patients who completed the dosing period, 20 (87%) achieved IGF-1 levels at the end of treatment that were within 20% of baseline or lower. Median IGF-1 values rose significantly after paltusotine washout (p 10%) included: headache, arthralgia, fatigue, peripheral swelling, paresthesia and hyperhidrosis. There were no discontinuations due to adverse events and no treatment related serious adverse events. These results suggest that patients with acromegaly treated with injected SRLs can switch to oral paltusotine while maintaining IGF-1 and that paltusotine appeared to be well tolerated.

BackgroundAdult GHD results from insufficient growth hormone (GH) secretion from the anterior pituitary gland and may represent either a continuation of childhood-onset GHD or GHD acquired during adulthood. Clinically, adult GHD is associated with central adiposity, decreased lean muscle mass, increased fat mass, decreased bone mineral density, and reduced quality of life. Current standard of care consists of GH replacement via daily injections. Lonapegsomatropin is a long-acting prodrug of somatropin (hGH), designed to deliver unmodified hGH with a weekly exposure profile. Lonapegsomatropin consists of somatropin that is transiently bound to a carrier via a proprietary TransCon Linker. The carrier extends the duration of somatropin in the circulation through a shielding effect that minimizes renal excretion and receptor-mediated clearance of the prodrug. At physiologic conditions, lonapegsomatropin releases fully active, unmodified somatropin via autocleavage of the linker in a controlled manner. The safety and efficacy of lonapegsomatropin have previously been evaluated in two phase 3 trials and one long-term extension trial in pediatric GHD. Changes in body composition are an objective and sensitive endpoint that reflects biologic activity of GH and clinical efficacy of GH replacement. Methods: The primary objective of the foresiGHt trial is to evaluate the efficacy of once-weekly lonapegsomatropin compared to placebo at 38 weeks in adults with GHD. The trial will be conducted at approximately 120 sites in North America, Europe, Asia, and Oceania. Approximately 240 subjects will be randomized 1:1:1 to once-weekly lonapegsomatropin, once-weekly placebo, or daily somatropin (Norditropin®). Subjects will be treatment-naïve or without GH therapy for at least 12 months. Subjects with well-controlled non-insulin dependent diabetes mellitus (HbA1c ≤ 7.5%) will be eligible. Following screening, the 38-week treatment period will consist of a 12-week gradual dose titration period and 26 weeks of fixed dose maintenance. Fixed dosing will be used to ensure maximal comparability across the treatment arms in the trial. Three dosing groups per arm will be established to allow for differences in age and oral estrogen intake in women. The primary endpoint is change from baseline in trunk percent fat at week 38, as measured by dual energy X-ray absorptiometry (DXA). Secondary efficacy endpoints are change from baseline in trunk fat mass and change in total body lean mass at week 38. Exploratory efficacy endpoints include total body fat mass, trunk lean mass, visceral adipose tissue, and patient-reported outcomes. Conclusion: The ongoing global phase 3 foresiGHt trial is designed to assess the efficacy, safety, and tolerability of lonapegsomatropin by weekly administration, compared to weekly placebo and daily hGH replacement therapy in adults with GHD.

Corticotroph adenomas, either secretory or silent, are associated with significant disease persistence and/or recurrence. Surgical resection is the first line treatment; however, recurrence rates range from 30 to 60%. Although several clinical parameters (i.e. postoperative cortisol level, tumor invasion) have been reported to predict tumor recurrence, none have high diagnostic accuracy. Granulation pattern classifies corticotroph tumors as densely granulated (DG) or sparsely granulated (SG) types, with the latter usually larger and more aggressively behaving. E-cadherin, a calcium-dependent adhesion molecule strongly expressed in normal pituitary cells, plays a role in epithelial cell behavior, tissue development, and suppresses epithelial-mesenchymal transition. Since loss of E-cadherin expression in sparsely granulated somatotroph pituitary tumors correlates with a more aggressive disease course, we sought to examine correlation between E-cadherin expression and behavior in densely versus sparsely granulated corticotroph tumors. A retrospective chart review of adult patients with corticotroph adenomas, seen at our institution between January 2012 - 2020 yielded 62 patients: 18 (29%) male and 44 female (71%), with median age at diagnosis of 49 years (range 25-82). Inclusion criteria required sufficient tissue for E- cadherin immunostaining (IHC). Microadenomas were identified in 19/62 (31%) patients, and 38/62 (52%) patients had clinical and biochemical findings consistent with excess cortisol secretion. Pre-operative imaging showed that 22/62 (35%) tumors were invasive into surrounding structures. After further classification as to densely granulated (DG) or sparsely granulated (SG) types by ACTH granulation pattern on IHC, 19/56 (34%) adenomas were SG, 37/56 (66%) were DG and 6 were not classified. E-cadherin staining was absent in 7/62 tumors (11%) and diminished in 5/62 (8%) tumors and staining did not correlate with dense versus sparse corticotroph types. Chi-squared analysis found a significant association between tumor size (greater than or less than 1cm) and secretion, with hormonally active more likely tumors to be microadenomas (p=0.004). Microadenomas were exclusively DG tumors (p

Background: Quality of life (QOL) in acromegaly has been a subject of interest in several published studies; however, there is no consensus on how QOL in patients who require medical treatment after surgery compares with those who achieve remission by surgery only. Aim: Quality of life after acromegaly treatment (QuaLAT) is a case-control questionnaire-based study with the aim to compare the QOL in those who were treated with surgery only with those who required medical treatment after surgery at a single tertiary centre for acromegaly. Methods: Patients with acromegaly attending endocrinology clinics were identified via our database. These were matched on the duration of disease into those who underwent surgery and went into disease remission biochemically (Group 1), and those who did not achieve biochemical remission after surgery and therefore required further medical treatment to control the disease (Group 2). Participants were then asked to fill three questionnaires to measure their QOL; Acromegaly Quality of Life Questionnaire (ACROQOL), and two generic questionnaires; 36-Item Short Form Survey (SF36) v2, and Fatigue Severity Scale (FSS). Results: 20 patients from each group participated in the study. The mean±SD duration of acromegaly (years) was similar in the two groups (9.8±6.9 vs 9.7±6.9 p=0.653). The majority of patients in the medical group were on somatostatin analogues, either alone or in combination (n=14), with four and two patients on cabergoline and pegvisomant alone respectively. There was no difference in QOL scores between groups 1 & 2, as measured by ACROQOL (mean score±SD 54.4±24.8 vs 55.3±26.1 p=0.765), SF36v2 (Physical component score 40.1± 11.1 vs 45.6±12.0 p=0.235; mental component score 41.7±13.0 vs 43.1±16.4 p=0.601), or FSS (mean score±SD 4.4±2.2 vs 4.5±2.0 p=0.985) questionnaires. There was no difference in ages between both groups and there were 75% females in group 1 and 45% in group 2. When compared with healthy controls as reported in the published literature, all three QOL scores were lower in our cohort [1-3]. Conclusions: Medical treatment achieves similar QOL to surgically treated acromegaly patients in remission in the long term. When compared with healthy controls, QOL remains worse in treated acromegaly patients. References:1. Webb, S.M., et al., Validity and clinical applicability of the acromegaly quality of life questionnaire, AcroQoL: a 6-month prospective study. Eur J Endocrinol, 2006. 155(2): p. 269-77.2. Jenkinson, C., et al., Assessment of the SF-36 version 2 in the United Kingdom. J Epidemiol Community Health, 1999. 53(1): p. 46-50.3. Ongre, S.O., et al., Progression of fatigue in Parkinson’s disease -A nine-year follow-up. Eur J Neurol, 2020.

Background: Cushing’s disease is a challenging endocrine disorder caused by non-physiological cortisol excess from adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. Inferior petrosal venous sampling (IPSS) is considered the gold standard investigation to differentiate Cushing’s disease from ectopic ACTH syndrome. Methods: This retrospective study included all patients who underwent IPSS between January 2011 and October 2020 at The National Hospital for Neurology and Neurosurgery in London. Patients demographics, radiological, surgical, endocrinological and, histological data were retrieved. We assessed the accuracy of IPSS in localizing ACTH secreting pituitary adenoma and its concordance with neuroimaging and surgical findings at the time of tumor resection. Results: In total 68 patients underwent IPSS, 22 males and 46 females. The median age was 42 years. IPSS was performed prior to primary surgery in 61 patients (90%) and before secondary surgery in 4 patients (6%). Three patients (4%) are awaiting surgery at the time of our study. Fifty-two patients (80%) had positive histology of ACTH expressing adenoma. Four patients (8%) had ectopic ACTH syndrome. The sensitivity of IPSS in predicting Cushing’s disease prior to corticotropin-releasing hormone (CRH) stimulation was 91% (95% CI [83% to 97%]) and accuracy of 88% (95% CI [77% to 95%]). The sensitivity of IPSS post CRH administration was 96% (95% CI [87% to 100%]) with accuracy of 86% (95% CI [75% to 93%]). Data on lateralization of pituitary adenoma were available for 63 patients. Prior to CRH stimulation, lateralization was right sided in 35 patients (56%), left sided in 15 (24%), and 13 patients (20%) did not have adequate interpetrosal sinus ACTH ratio. Lateralization post CRH stimulation was right sided in 40 patients (64%), left sided in 20 (32%), and 3 patients (4%) did not achieve adequate ACTH gradient ratio between two sides. Eighteen patients (30%) switched adenoma lateralization between pre and post CRH stimulation. Post CRH IPSS was consistent with neuroradiology in localizing pituitary adenomas in 59% (29 out of 49 patients) and concordant with surgical findings in 41% (25 out of 61 patients). Patients with ectopic ACTH syndrome had negative IPSS at all stages. IPSS procedure failed in 2 patients (3%). No post procedure complications were reported. Conclusion: IPSS has high sensitivity in diagnosing pituitary driven Cushing’s disease with good safety profile. However, the reliability in lateralizing pituitary adenoma is debated. One third of patients in this cohort switched lateralization before and after CRH administration. Studies on monkeys and rats showed that CRH induces coronary vasodilation and reduction in systemic vascular resistance. This suggest that CRH might have vasoactive effect on pituitary blood vessels with subsequent influence on IPS:P ACTH gradient ratio between the two sides.

Context: Interleukin-2 (IL2), a proinflammatory cytokine, is used for treatment of malignancies. Increased cortisol and ACTH were noted, but GH secretion was not investigated in detail. This is the first study in healthy men which uses moderate high IL2 doses as used in cancer treatment. Objective: The goal of this study was to quantify GH secretion after a single sc injection of IL2 in young and older healthy men in relation to dose, age and body composition. Design: This was a placebo-controlled, blinded, prospectively randomized cross-over study in 17 young subjects (mean age 24.1 yr) and 18 older subjects (mean age 63.9 yr). The subjects underwent 24 h of blood sampling at 10-min intervals, starting at 1800 h. At 2000 h IL2 (3 or 6 million units per m2 body surface) or saline was injected sc. Lights were off between 2300 and 0700 h. Outcome Measures: Deconvolution analysis of GH. Abdominal visceral fat (AVF) was calculated from single slice CT. Results: GH secretion (pulsatile and total) was negatively related to AVF (R=0.67, P

Background: The standard first-line therapy for clinically nonfunctioning adenomas (NFPA) is transsphenoidal surgery, however there is no consensus of the optimal postsurgical treatment for residual adenoma. Medical therapy, such as cabergoline (CAB), may be an alternative for preventing growth of postoperative pituitary tumor remnants. The moment of introduction dopamine agonist (DA) is still uncertain. Objective: To assess tumor behavior in patients who used CAB in the postoperative period. Design and methods: A retrospective cross-sectional study was performed with twenty one patients with NFPA treated surgically. All patients stayed with residual tumor and were divided in two groups: patients who received CAB early in postoperative period (Group A, n=6) and when tumor growth were detected during follow-up (Group B, n=15). CAB dosage was 1.5mg or 3.5mg per week. A change in tumor size was considered significant and recorded as such if a difference of at least 5 mm in major diameter was observed. MRI was performed four months after surgery and yearly thereafter in all patients. Subjects in treatment groups also underwent MRI 6 months following medical therapy. No patients were treated by irradiation before or during the follow-up. Statistical analysis was performed using the Fisher’s exact test. Results: From 21 patients, 11 were men and 10 women with similar mean age in two groups (p=0.651). MRI in group A showed stabilization of residual tumor in 50% (3/6) and tumor reduction in 50% (3/6) in group A. In group B, tumor shrinkage was observed in 47% (7/15), stabilization in 27% (4/15) and enlarged in 27% (4/15). No statistical difference between groups was obtained regarding tumor shrinkage and stabilization with the treatment (Group A n=6 versus Group B n=11, p=0.281). In contraste Batista et al., 2016, have already shown that CAB was effective alternative in residual tumor reduction in a study with 74 patients. Conclusion: A multicenter study is necessary to define the role of CAB in the treatment of residual tumor in postsurgical patients with NFPA.

Endogenous Cushing’s syndrome (CS) is a rare, serious disorder caused by chronic cortisol excess. A phase 3, open-label study (SONICS) demonstrated efficacy and safety of levoketoconazole in adults with CS. LOGICS is a phase 3, double-blind (DB), placebo-controlled, randomized-withdrawal (R-W) study that investigated levoketoconazole in adults with CS via an open-label titration-maintenance (T-M) phase (14-19 weeks) followed by a DB R-W phase (~8 weeks) and a restoration phase (~8 weeks). The primary endpoint is the proportion of patients with loss of mean urinary free cortisol (mUFC) response during R-W (ie, mUFC ≥1.5x ULN or mUFC >40% above baseline if baseline was >1.0x ULN, or other rescue criterion met). Key secondary endpoints include mUFC normalization and changes in comorbidity biomarkers at the end of R-W. Of 84 patients dosed in LOGICS (12 SONICS-completers and 72 de novo), 79 were titrated (72 de novo) and 44 patients (39 from T-M and 5 direct roll-overs from SONICS) were randomized 1:1 to receive levoketoconazole (n=22) at an individualized therapeutic dose or a matching placebo regimen (n=22). The R-W population mean age was 44.3 years, 77% were female, 91% were white, mean weight was 83.2 kg, and 86% had Cushing’s disease. Selected results from an interim analysis at the end of R-W are presented. At the end of R-W, significantly more patients on placebo (95.5%) achieved primary endpoint of loss of mUFC response than those who continued on levoketoconazole (40.9%) (treatment difference [TD], -54.5%; 95% CI: -75.7, -27.4; P=0.0002). Similarly, the mUFC normalization rate at the end of R-W was significantly higher for levoketoconazole (50.0%) versus placebo (4.5%; TD, 45.5%; 95% CI: 19.2, 67.9; P=0.0015). Mean change from R-W baseline to end of R-W in total cholesterol was -1.4 mg/dL for levoketoconazole and +35.6 mg/dL for placebo (P=0.0004); mean change in LDL cholesterol was -0.2 mg/dL and +25.0 mg/dL, respectively (P=0.0056). Mean change in glycemia markers and high sensitivity C-reactive protein were not significantly different between treatment groups. 90% of levoketoconazole-treated patients across the T-M and R-W phases (n=80) had ≥1 treatment-emergent adverse event (AE); AEs led to treatment discontinuation in 19% (15/80) of patients, 11% (9/80) of which were considered treatment-related. The most common AEs were nausea (29%), hypokalemia (28%), and headache (21%); serious AEs drug related were reported in 4 patients (3 liver-related, 1 gastroenteritis, 1 hypokalemia); AEs of special interest included liver-related (11%), QT prolongation (10%), and adrenal insufficiency (10%). These LOGICS interim results confirm the safety and efficacy findings from SONICS, establishing treatment benefit as levoketoconazole specific. This evidence further supports the use of levoketoconazole as an important treatment option for endogenous CS. Support: Strongbridge Biopharma.

Background: MPOWERED, a large phase 3 trial, assessed maintenance of response to oral octreotide capsules (OOC; MYCAPSSA®) compared to injectable somatostatin receptor ligands (iSRLs) in patients with acromegaly who responded to OOC and iSRLs (octreotide or lanreotide). OOC were recently approved in the US for patients with acromegaly who responded to and tolerated iSRLs. Methods: Eligibility criteria included age 18-75 years at screening, acromegaly diagnosis, disease evidence, biochemical control (insulin-like growth factor I [IGF-I] Results: Of 146 enrolled patients, 92 entered the RCT (OOC, n=55; iSRLs, n=37). Both arms were well balanced for age, sex, and acromegaly duration. OOC demonstrated noninferiority to iSRLs in maintaining biochemical response, with 91% (CI, 80%-97%) of OOC and 100% (CI, 91%-100%) of iSRL groups maintaining control during the RCT. Of those responding at end of Run-in, 96% of patients on OOC maintained response during RCT. Using nonresponse imputation, 89% of OOC and 95% of iSRL groups were biochemically controlled in RCT. Landmark analysis of those respnding at end of Run-in showed that 94% of patients in each group maintained response at RCT end. In both groups, IGF-I levels were stable in the RCT, average IGF-I at baseline and RCT end being 0.9 × ULN (OOC) and 0.8 × ULN (iSRL). Mean change in GH from RCT start to RCT end was -0.03 ng/mL (OOC) and +0.29 ng/mL (iSRL). Safety data were mostly similar between groups; the OOC group did not experience injection site reactions. Conclusion: In this noninferiority trial in patients with acromegaly, OOC demonstrated maintenance of biochemical response compared to iSRLs. Results support the efficacy of OOC as a possible iSRL alternative.