Pivonello, Rosario

Abstract Context Biochemical test results are central to clinical decision-making for the diagnosis and management of Cushing syndrome (CS). With emerging research and increasing availability of different tests, updated consensus on the utility of these biomarkers is warranted. Objective To establish an updated consensus on the role of biomarkers in the diagnosis and monitoring of adrenocorticotropic hormone-dependent CS, address novel therapeutic approaches, and identify areas for future research. Design A modified 2-round Delphi panel was conducted. Consensus was defined as ≥70% agreement/disagreement for Likert-scale statements or ≥70% selection of the same option for single-choice questions. Setting Participants represented a range of international expertise. Participants Forty-one participants took part in the Delphi panel, with no attrition between rounds (one nonclinician was not required to complete the second round). An 8-member Steering Committee guided statement development. Results Of statements designed to reach consensus, 45% (14/31) and 44% (11/25) statements reached consensus in Rounds 1 and 2, respectively. Notably, most panelists reported the use of late-night salivary cortisol for diagnosis of mild CS and for monitoring following pituitary surgery or medical or radiation therapy. Most panelists responded that block-and-replace therapies can be considered in patients with cyclical or severe CS, and consensus was reached that restoration of circadian rhythm is a treatment goal for patients with CS. Conclusion Areas of alignment among experts on the diagnosis and monitoring of CS are presented. The findings from this study are intended to support clinicians in their clinical decision-making and highlight priority areas for future research.

Abstract Disclosure: I. Bancos: None. H. Falhammar: None. J. Young: None. R. Pivonello: Received research funding from Corcept Therapeutics, Neurocrine Biosciences, Recordati AG, Spruce Bioscience and Xeris Pharmaceuticals (Strongbridge Biopharma), Consultant for Corcept Therapeutics, Crinetics Pharmaceuticals, HLundbeck A/S and Recordati Rare Diseases.. G. Russo: None. M.R. Stancampiano: None. V.H. Lin: Full-time employee of Neurocrine Biosciences, Inc. J. Sturgeon: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. Background: In patients with classic congenital adrenal hyperplasia (CAH), chronic glucocorticoid (GC) treatment, especially at supraphysiologic doses, can lead to weight gain or obesity. Crinecerfont, a corticotropin releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to GC replacement to control androgens in patients with CAH. In CAHtalyst™ Adult (NCT04490915), least-squares mean (LSM) percent changes in GC dose at Week 24 (end of double-blind placebo-controlled [DBPC] period) indicated a significant reduction with crinecerfont (-27.3% vs 10.3% for placebo; LSM difference [LSMD] -17.0%; P<0.0001) while androstenedione was maintained or improved relative to Day 1 baseline (BL). At Month 12 (end of open-label [OL] period), mean percent decreases from BL were -24.6% in participants continuing crinecerfont (CFT/CFT) and -29.7% in those switched from placebo (PBO/CFT). Objective: To evaluate weight-related outcomes in adults with CAH who received up to 1 year of crinecerfont. Methods: Mean change from Day 1 BL in body mass index (BMI) and mean percentage change from BL in weight were analyzed at Week 24 and Month 12. Achievement of >5% reduction in weight was also analyzed, with results presented as % (n/N: n=number meeting response threshold, N=number who were overweight/obese [BMI ≥25 kg/m2]) at BL and had available data at assessment [Week 24 and Month 12]). For predefined endpoints in the DBPC period, results are presented as LSM changes with LSMD and P-value. Results: Mean BMI at BL was 30.1 kg/m2 (crinecerfont) and 29.0 kg/m2 (placebo), and >70% of participants were overweight or obese (74.6% [91/122] crinecerfont; 63.3% [38/60] placebo). At Week 24, LSM changes from BL for crinecerfont vs placebo were as follows: BMI (-0.42 vs -0.02; LSMD: 0.40, P=0.1068); percent change in weight (1.45% vs -0.07%; LSMD: 1.38%, P=0.0856). At Month 12, further mean reductions from BL were observed with crinecerfont in BMI (-0.81 kg/m2 CFT/CFT, -0.44 kg/m2 PBO/CFT) and weight (-2.72% CFT/CFT, -1.37% PBO/CFT). Among participants who were overweight or obese at BL, a higher percentage achieved >5% reduction in weight at Week 24 with crinecerfont 18.4% (16/87) versus placebo 13.5% (5/37). At Month 12, 27.4% (23/84) and 38.9% (14/36) achieved this threshold in the CFT/CFT and PBO/CFT groups, respectively. Conclusion: Adults with CAH who received up to 1 year of crinecerfont showed reductions in BMI and weight. Among participants who were overweight or obese at BL, 30.8% achieved a >5% reduction in weight at Month 12. These analyses indicate that the substantial GC dose reductions enabled by crinecerfont can allow for improvements in the weight-related effects associated with chronic supraphysiologic GC exposure. Presentation: Sunday, July 13, 2025

Abstract Objective To study pregnancy outcomes and complications in women with congenital adrenal hyperplasia (CAH). Methods A retrospective multicenter study was conducted at tertiary reference centers in 5 countries (Austria, Germany, Italy, Sweden, USA), including 72 adult women with CAH (nonclassic [NC] n = 34, simple virilizing [SV] n = 21, salt wasting [SW] n = 17). Results A total of 133 pregnancies, 112 live births, and 25 abortions were documented. Prolonged latency to pregnancy was observed (median 11 months in SW, 24 months in SV, 8 months in NC), with a notable use of fertility-enhancing medication (25.6%) and assisted reproductive techniques (30.8%). Over half of the women in each group took more than 12 months to conceive. The average number of live births (1.4-1.6 children per woman) was similar across CAH phenotypes and comparable to the general population. Spontaneous abortion rates (18.0%) were also similar across phenotypes. Primary cesarean section rates (60.9%) were higher than in the general population, though 23.8% of women with SV and 29.4% of women with SW gave birth naturally, despite most having undergone genital surgery. Children categorized as small for gestational age were 20.5%. Pregnancy, delivery, and postpartum complications were rare for mothers and neonates. Conclusion The study indicates a prolonged latency to pregnancy and high use of fertility treatments in CAH patients, regardless of phenotype. Abortion rates were not increased, and overall pregnancy and perinatal outcomes were favorable.

Abstract Disclosure: R.J. Auchus: Consulting Fee; Self; Neurocrine Biosciences, Inc., Crinetics Pharmaceuticals, OMass Therapeutics, H Lundbeck A/S, Adrenas Therapeutics. Research Investigator; Self; Neurocrine Biosciences, Inc., Diurnal, Crinetics Pharmaceuticals, Spruce Biosciences. O. Hamidi: Advisory Board Member; Self; Corcept Therapeutics, Recordati Rare Diseases, Amryt Pharma, Neurocrine Biosciences, Inc., Xeris, Lantheus. R. Pivonello: Advisory Board Member; Self; Corcept Therapeutics, Recordati AG, Crinetics Pharmaceuticals, H. Lundbeck A/S. Research Investigator; Self; Corcept Therapeutics, Recordati AG, Strongbridge Biopharma, Neurocrine Biosciences, Inc. I. Bancos: Consulting Fee; Self; Corcept Therapeutics, Recordati Rare Diseases, HRA Pharmaceuticals, Neurocrine Biosciences, Inc., Diurnal, Spruce Biosciences, Sparrow Pharmaceuticals, Adrenas Therapeutics. Research Investigator; Self; Recordati Rare Diseases. G. Russo: Advisory Board Member; Self; Novartis Pharmaceuticals, Sandoz, Diurnal. Speaker; Self; Novartis Pharmaceuticals, Sandoz, Diurnal. S.F. Witchel: Research Investigator; Self; Neurocrine Biosciences, Inc. A.M. Isidori: Research Investigator; Self; Pfizer, Inc., Merck Serono, HRA Pharmaceuticals, Recordati AG, Corcept. P. Rodien: Consulting Fee; Self; Pfizer, Inc., Novo Nordisk, Lilly USA, LLC, Ipsen, HRA Pharmaceuticals, IBSA Pharma, Recordati Rare Diseases. U. Srirangalingam: Advisory Board Member; Self; Diurnal. Speaker; Self; Diurnal. F.W. Kiefer: Advisory Board Member; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. Speaker; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. H. Falhammar: Consulting Fee; Self; Diurnal, Roche Diagnostics, Neurocrine Biosciences, Inc., H Lundbeck A/S, Adrenas Therapeutics. D.P. Merke: Research Investigator; Self; Diurnal, Adrenas Therapeutics, Neurocrine Biosciences, Inc. N. Reisch: Consulting Fee; Self; Diurnal, Crinetics Pharmaceuticals, Neurocrine Biosciences, Inc., Spruce Biosciences, H Lundbeck A/S. J. Sturgeon: Employee; Self; Neurocrine Biosciences, Inc. E. Roberts: Employee; Self; Neurocrine Biosciences, Inc. V.H. Lin: Employee; Self; Neurocrine Biosciences, Inc. J.L. Chan: Employee; Self; Neurocrine Biosciences, Inc. R. Farber: Employee; Self; Neurocrine Biosciences, Inc.. Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a genetic disorder characterized by cortisol deficiency and excess adrenal androgens, typically requires management with supraphysiological glucocorticoid (GC) doses. Crinecerfont is a novel oral CRF1 antagonist that reduced elevated adrenocorticotropic hormone and adrenal androgens in patients with 21OHD in 14-day open-label Phase 2 studies. This Phase 3 study (CAHtalyst: NCT04490915) evaluated whether crinecerfont can reduce daily GC dose while maintaining androgen control in adults with 21OHD. Methods: Adults (≥18 years) with 21OHD, stable GC regimens at doses >13 mg/m2/d in hydrocortisone equivalents (HCe), and normal or elevated androstenedione (A4) were randomized (2:1) to crinecerfont 100 mg BID or placebo for 24 weeks. GC dosing was maintained stable for 4 weeks, followed by a planned GC down-titration over 8 weeks to achieve a GC dose of 8-10 mg/m2/d. GC doses were adjusted as needed during the last 12 weeks to maintain A4 control (≤120% of baseline or ≤upper limit of normal [ULN]) by week 24. Results: In the 182 randomized participants (51% male, mean age 31 years), demographics and baseline characteristics were similar between treatment arms (122 crinecerfont, 60 placebo). Mean GC dose at baseline was 17.6 mg/m2/d HCe (32 mg/d), with 58% on HC alone, 29% taking predniso[lo]ne, and 13% taking dexamethasone; mean pre-GC A4 (620 ng/dL) was elevated >2-3-fold the ULN. Over 95% of participants completed the double-blind treatment period. At week 24, the crinecerfont arm had a significantly greater percent reduction in GC dose while maintaining A4 control vs placebo (-27% vs -10%; least squares mean difference [LSMD]: -17%; p<0.0001) (primary endpoint). At week 4 (end of GC-stable period), a greater reduction in A4 prior to the morning GC dose was observed with crinecerfont vs placebo (LSMD: -345 ng/dL; p<0.0001) (key secondary endpoint). At week 24, a higher percentage of participants reached a protocol-defined physiological GC dose (≤11 mg/m2/d) while maintaining A4 control with crinecerfont (63% vs 18% for placebo; p<0.0001) (key secondary endpoint). The most common treatment-emergent adverse events (AEs) in the crinecerfont arm were fatigue (25% vs 15% for placebo), headache (16% vs 15%), and COVID-19 (14% vs 9%). There were few serious AEs (3% overall), with none assessed as related to the study drug. Conclusions: Crinecerfont, an oral CRF1 antagonist, represents a novel treatment option to improve androgen control for patients with 21OHD. In the largest interventional Phase 3 study conducted to date in adults with 21OHD, crinecerfont led to a significant reduction in A4 while GC dose was stable, enabling a significant percent reduction in GC dose while maintaining A4 control at 24 weeks. Crinecerfont was overall well tolerated. Presentation: 6/1/2024

Abstract Disclosure: I. Bancos: Advisory Board Member; Self; Adrenas, Diurnal, Neurocrine, Spruce, HRA Pharmaceuticals, Sparrow, Recordati Rare Diseases, Xeris, Novo Nordisk, AstraZeneca, Corcept. Consulting Fee; Self; Adrenas, Diurnal, Neurocrine, Spruce, HRA Pharmaceuticals, Sparrow, Recordati Rare Diseases, Xeris, Novo Nordisk, AstraZeneca, Corcept. Grant Recipient; Self; Recordati, HRA Pharmaceuticals. Other; Self; Adrenas, Diurnal, Neurocrine, Spruce, HRA Pharmaceuticals, Sparrow, Recordati Rare Diseases, Xeris, Novo Nordisk, AstraZeneca, Corcept. E.B. Geer: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; Lundbeck, Crinetics, HRA Pharmaceuticals, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Xeris Pharmaceuticals (Strongbridge), Corcept, Recordati Rare Diseases, Sparrow. F. Castinetti: Consulting Fee; Self; HRA Pharmaceuticals, Recordati. Grant Recipient; Self; HRA Pharmaceuticals, Recordati. R. Feelders: Advisory Board Member; Self; Recordati. Consulting Fee; Self; HRA Pharmaceuticals, Recordati. Grant Recipient; Self; Corcept Therapeutics. M. Fleseriu: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). R. Pivonello: Consulting Fee; Self; Corcept Therapeutics, Recordati, Crinetics Pharmaceuticals, H Lundbeck. Grant Recipient; Self; Recordati, Corcept Therapeutics, Xeris Pharmaceuticals (Strongbridge), Neurocrine Biosciences. M. Reincke: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; Recordati Rare Diseases, HRA Pharmaceuticals, Lundbeck, Crinetics. Grant Recipient; Self; Recordati Rare Diseases, HRA Pharmaceuticals, Lundbeck, Crinetics. Speaker; Self; Recordati Rare Diseases, HRA Pharmaceuticals, Lundbeck, Crinetics. A. Tabarin: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; H Lundbeck, Crinetics, HRA Pharmaceuticals, Recordati Rare Diseases. J. Le Mouhaër: Employee; Self; Recordati. J. Stermenska: Employee; Self; Recordati. M. Maldonado: Employee; Self; Recordati. B.M. Biller: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; H Lundbeck, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Introduction: Osilodrostat, a potent oral 11β-hydroxylase inhibitor, provides control of cortisol production and improves outcomes in patients (pts), as shown by the clinical development program of Cushing’s disease (CD; Fleseriu M et al. Lancet Diabetes Endocrinol 2021;9:847-75) leading to EMA approval for Cushing’s syndrome (CS) and FDA approval for CD. The prospective LINC 6 study (NCT05382156) evaluates long-term safety and efficacy of osilodrostat in routine clinical practice over a 3-­year follow-up of CS pts. Here, we report 1-year interim data. Methods: Pts aged ≥18 years with endogenous CS are being enrolled in countries where osilodrostat is approved and available (including USA and Europe), irrespective of prior osilodrostat use. Treatment decisions and follow-up are at investigator discretion. The primary endpoint is incidence of osilodrostat-related adverse events (AEs) and serious AEs, focusing on AEs related to hypocortisolism, accumulation of adrenal hormone precursors, QT prolongation and pituitary tumor enlargement. Secondary endpoints include change in mean urinary free cortisol (mUFC), serum cortisol and late-night salivary cortisol (LNSC). Evaluation of biochemical parameters is recommended at baseline, months 1 and 3, and every 3 months thereafter, as available. AEs are recorded at baseline and each visit. Analyses are descriptive. We report change for pts with assessments at baseline and every 3 months. Results: Of 106 pts enrolled at the 1-year interim analysis, 94 were included in the safety population: CD, n=78; non-CD CS, n=16 (adrenal adenoma, n=3; adrenal hyperplasia, n=3; ectopic, n=9; other, n=1). Mean (SD) age was 53.2 years (12.7); 70.2% (n=66) were female. Median (min-max) osilodrostat exposure and dose were 5.5 months (0.1-13.9) and 5.0 mg/day (1.0-60.0). 29 pts reported 109 AEs; 12 pts reported 44 AEs that were considered treatment related. Overall, the most common (≥5%) AEs were asthenia and vomiting (both n=6/109; 5.5%); treatment-related AEs with highest frequency were vomiting and dizziness (both n=4/44; 9.1%). 7 AEs led to discontinuation in 4 pts; 5 AEs were considered osilodrostat related (nausea and vomiting in 1 pt; worsening hypertension, uncontrolled blood pressure and dizziness in another) and 2 were not (pituitary tumor surgery and right adrenalectomy). AEs related to hypocortisolism, accumulation of adrenal hormone precursors, QT prolongation and pituitary tumor enlargement occurred in 7 (7.4%), 4 (4.3%), 2 (2.1%) and 0 pts, respectively. At month 3, mUFC, serum cortisol and LNSC were normalized in 71.4% (n=10/14), 69.2% (n=18/26) and 50.0% (n=7/14) of pts. Conclusions: Results from this real-world clinical setting show that osilodrostat is generally well tolerated and provides early improvements in mUFC and LNSC in pts with endogenous CS, building on evidence from the previous randomized, controlled trials LINC 3 and LINC 4. Presentation: 6/3/2024

Background Corticotroph tumor progression (CTP) leading to Nelson’s syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing’s disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing. Methods A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018. Results Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients). Conclusions We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2–4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension

Abstract Context Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment. Objective Multicenter survey on current clinical approaches in managing AI during pregnancy. Design Retrospective anonymized data collection from 19 international centers from 2013 to 2019. Setting and Patients 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%). Results Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes. Conclusions This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.