Citations

Abstract Disclosure: R. El Mouallem: None. T. McKenzie: None. A.N. Lteif: None. Background- Pancreatic neuroendocrine tumors (PNETs) are rare, but their incidence is rising. Ethanol ablation is increasingly used in adult patients with insulinomas or small nonfunctional PNETs, particularly in patients who are ineligible for surgical resection. Ethanol ablation of a PNET has not been previously reported in the pediatric population. Clinical Case- A 12-year-old female with known multiple endocrine neoplasia type 1 (MEN1) and multifocal PNETs presented for evaluation of a 1.3 cm nonfunctional, Dotatate avid pancreatic uncinate lesion. A CT angiogram of the pancreas revealed an arterially enhancing 1.3 cm nodule, which measured 8 mm one year prior. There was no evidence of metastatic disease. Given the increasing size of the lesion and young age of the patient, operative intervention was pursued. Due to the depth of the lesion and its proximity to the pancreatic duct during operative pancreas ultrasonography, surgical enucleation was deemed non-feasible. During the procedure, 7 additional subcentimeter pancreatic lesions concerning for PNETs were identified in the pancreatic body, tail, head and neck-body junction. Ultrasound guided ethanol ablation of the primary lesion was performed. Follow-up imaging demonstrated a promising response. 7 months post ablation, a Dotatate PET CT scan showed persistent focal uptake in the region of the ablated nodule. However, by 9 months, MRI abdomen revealed a decrease in the size of the lesion, now measuring 6 mm, with stable Dotatate uptake. By 19 months post ethanol ablation, the previously hyper-enhancing lesion was no longer visible on MRI, demonstrating complete structural resolution. Conclusion- This case demonstrates that ethanol ablation is a promising treatment option for PNETs in the pediatric population. Given the complexities of surgical resection in children, particularly for deep or anatomically challenging lesions, ethanol ablation offers a potentially less morbid alternative with encouraging outcomes. Further research may establish this approach as a viable option for select pediatric patients. Presentation: Sunday, July 13, 2025

Abstract Disclosure: S.R. Chacko: None. J. Saini: None. S. Sharma Sharma: None. S. Ahmadian: None. S.J. Achenbach: None. E. Atkinson: None. V. Fell: None. J.J. Van Gompel: None. W.F. Young, Jr.: None. I. Bancos: None. Context: Evidence on the duration of postoperative adrenal insufficiency (AI) in patients with endogenous hypercortisolism is scarce. Objective: To determine the duration of postoperative AI and to identify factors associated with the duration of AI in patients undergoing surgery for endogenous hypercortisolism.Methods: We conducted a single center prospective cohort study, 2019-2024, of patients with endogenous hypercortisolism [Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS)] treated with surgery. Associations of demographics, BMI, clinical and biochemical hypercortisolism severity, subtype of hypercortisolism, presurgical hypercortisolism duration and glucocorticoid type in relation to duration of AI were investigated. Results: The 110 patients [36% MACS, 46% pituitary CS, 15% adrenal CS, 3% ectopic CS, median age 50 years (IQR: 40-60), 82% women] who developed postsurgical AI were followed for a median duration of 26 months (IQR: 15-38). By the end of follow up, 96 patients (87%) had recovery of AI. The median time to recovery of AI was shorter in MACS vs. Overt Cushing syndrome (3.0 months (95% CI: 2.5-6.2) vs. 12.3 months (95% CI 9.0-17.3), P =0.002). Biochemical severity score (r=0.32, P=0.002) and duration of preoperative hypercortisolism symptoms (r=0.29, P=0.005), but not age, sex, BMI, clinical severity, or glucocorticoid type were associated with the duration of AI. We found no differences in the duration of AI between patients with ACTH-dependent vs ACTH-independent CS (12.3 months (95% CI: 6.0-17.2) vs 13.9 months (95% CI: 9.0-25.5), P =0.7).Conclusion: In this interim analysis, we showed that after surgical remission of endogenous hypercortisolism, duration of postoperative AI was longer in CS compared to MACS. Additionally, higher biochemical hypercortisolism severity score and a longer duration of symptoms suggestive of hypercortisolism were associated with a longer duration of postoperative AI. Presentation: Sunday, July 13, 2025

Abstract Disclosure: D. Hassan: None. M. Salama: None. S. Kumar: None. K. Muthusamy: None. Background: Obesity is prevalent among individuals with Bardet-Biedl Syndrome (BBS), affecting approximately 72%-86% of patients. Setmelanotide, an MC4R agonist, is approved for the treatment of obesity in patients with BBS. It reduces hyperphagia and improves quality of life. However, the high cost of setmelanotide and the need for daily injections limit its use. Affordable and effective alternative pharmacotherapies are needed for managing obesity in patients with BBS. Here, we present a case of an adult with BBS who experienced significant weight loss following treatment with a combination of topiramate and phentermine. Clinical Case: A 29-year-old Hispanic female with BBS due to a homozygous BBS2 mutation (NM_031885.3, c.717+1G>T, GT donor) was evaluated for migraine. BMI was elevated at 42.5 kg/m², and obesity was complicated by obstructive sleep apnea, chronic respiratory failure requiring supplemental oxygen with activity, impaired fasting glucose (101 mg/dL; reference range [RR]: 70-100 mg/dL), and dyslipidemia (triglycerides: 252 mg/dL [RR: 30-150 mg/dL]; very low-density lipoprotein (VLDL): 50.4 mg/dL [RR: 8-30 mg/dL]; total cholesterol: 190 mg/dL [RR: 0-200 mg/dL]; high-density lipoprotein (HDL): 40 mg/dL [RR: 40-60 mg/dL]). She had polydactyly, retinal dystrophy, developmental delay and subclinical hypothyroidism. Topiramate was initiated at 25 mg and subsequently increased to 50 mg. At 31 years of age, BMI was 40.5 kg/m², and weight had decreased by 7.5 kg after two years of therapy with topiramate and lifestyle interventions. Phentermine 30 mg daily was added. She experienced a notable appetite-suppressing effect, reduced nighttime eating, fewer sugar cravings, and decreased stress-related eating. She was able to extend the duration of exercise with improved endurance. She reported constipation as a side effect but had no other intolerances. After three months of phentermine therapy, BMI decreased to 34.96 kg/m². Repeat metabolic profile revealed fasting glucose 70 mg/dL, HbA1c 5.5% (RR: 4.5-5.6%), triglycerides 204 mg/dL, VLDL 40.8 mg/dL, total cholesterol 175 mg/dL, HDL 38 mg/dL, and low-density lipoprotein (LDL) 96 mg/dL (RR: 70-100 mg/dL). Eight months after starting phentermine, BMI further decreased to 32.31 kg/m², reflecting a 25% total weight loss. Conclusion: This case report highlights the excellent weight loss response (25% total weight loss) and significant improvement in metabolic profile with phentermine and topiramate combination therapy in a patient with BBS. The effects of this combination therapy have not been formally studied in BBS, emphasizing the need for further research to evaluate the efficacy of conventional anti-obesity medications—used alone, sequentially, or in combination with setmelanotide—to optimize weight and metabolic outcomes. Keywords: Bardet-Biedl Syndrome, obesity, topiramate, phentermine, weight loss. Presentation: Sunday, July 13, 2025

Abstract Disclosure: J.R. Hewlett: None. J.G. Sfeir: None. R.A. Wermers: None. J.J. Schmitz: None. Percutaneous ethanol ablation (PEA) is a non-surgical technique used in the management of hyperparathyroidism (HPT) since the 1980s. Previously published cohorts are small and/or focused on patients with primary hyperparathyroidism (PHPT) in the setting of multiple endocrine neoplasia type 1 (MEN1). New randomized controlled trial data suggests similar response rates between parathyroidectomy and PEA (98.5% vs 91.1%) for uniglandular disease, and a previously published cohort of PEA in patients with MEN1 and recurrent multiglandular PHPT at our institution reported post-PEA normocalcemia in 74.5% of patients. This retrospective cohort study examined the treatment response to PEA in those with PHPT (including MEN1) and tertiary HPT (THPT) at a single institution between 1997-2023. Those with secondary hyperparathyroidism or eucalcemic PHPT were excluded. The primary outcome was a serum calcium ≤10.1 mg/dL at 3-6 months and secondary outcomes included number and volume of ethanol injections, time to recurrence of HPT, and complications of PEA. A total of 83 patients were included. Most were women (62.7%) and the median age at diagnosis of HPT was 40 years. The majority had PHPT (90.4%), and many (86.7%) had previously undergone surgery. The most common indications for PEA were risk for hypoparathyroidism with additional surgery (72.3%) poor surgical candidacy (16.9%), and patient preference (8.4%). The mean calcium was 10.7 mg/dL (95% CI 10.56-10.85) and the mean PTH was 164 pg/mL (95% CI 120.6-208.3) prior to PEA. The mean number of ethanol injections was 3.0 (95% CI 2.6 – 3.4) and the cumulative volume of ethanol was 1.2 mL (95% CI 1.0-1.4). At 3-6 months, 68.3% of treated patients had calcium ≤10.1 mg/dL with a mean value of 9.4 mg/dL (95% CI 9.1-9.6). Of those, 42% did not have recurrence at most recent follow-up. Of those with recurrence, a post-PEA calcium ≤10.1 mg/dL at 3-6 months was associated with a longer time to recurrence than those without (36.9 months versus 3.75 months; P=0.0009). There was no significant difference between the number of times (P=0.56) or the volume (P=0.41) of ethanol injected between those with calcium of ≤10.1 mg/dL at 3-6 months and those without. Hypocalcemia was observed in 8 (9.6%; transient in 75%), hypoparathyroidism in 3 (3.6%; transient in 66.7%), laryngeal nerve injury in 2 (2.4%; transient in 50%), and hoarseness in 9 (10.8%; transient in 100%) patients. This is the largest North American cohort of patients who received PEA for HPT and represents a broader review of HPT than previously published. Our rate of post-PEA eucalcemia is lower than previously reported, however this cohort was complex with a high proportion of multiglandular disease (80.7%), MEN1 (39.8%) and prior surgeries (mean 1.7 per person; 95% CI 1.5-1.9). PEA remains a safe and effective treatment for patients with recurrent HPT, especially those at high risk of post-surgical hypoparathyroidism. Presentation: Monday, July 14, 2025

Abstract Disclosure: P. Hopmann: None. S. Lund: None. T. Foster: None. B. Dy: None. T. McKenzie: None. G. Johnson: None. R.A. Wermers: None. M. Lyden: None. Background: Previous studies have demonstrated that C11 choline positron emission tomography/computed tomography (Choline-PET/CT) can localize abnormal parathyroid glands in the re-operative setting. This study assesses a large volume of patients with primary hyperparathyroidism (1HPT) who underwent Choline-PET/CT to confirm its utility in the setting of negative or equivocal conventional imaging. Methods: All patients who underwent Choline-PET/CT for evaluation of 1HPT from July 2017 to July 2024 at a single institution were reviewed. Inclusion criteria were patients who underwent parathyroidectomy and had lab testing to assess for cure (defined as >50% drop from baseline PTH and into normal range, or resolution of hypercalcemia at follow-up). Sensitivity, positive predictive value (PPV), false negative rate (FNR), and accuracy were compared to conventional imaging (neck ultrasound, parathyroid scan, and parathyroid four-dimensional CT (4D-CT)). Subgroup analysis was conducted comparing sensitivity of modalities among index operations, and separately in re-operations. Results: 176 patients were identified. 85 underwent parathyroidectomy, 1 patient was excluded due to lacking data to evaluate for cure. Of 91 patients who did not undergo parathyroidectomy, 45 were non-localizing on all imaging, and 46 had positive Choline-PET/CT findings but opted against surgery due to mild disease or prohibitive re-operative risk. Of the included 84 parathyroidectomy patients, 61 failed to localize on at least one conventional modality, and 15 failed to localize on all conventional studies. 67 patients (80%) achieved cure, of whom 53 were re-operations (range of 1-4 prior operations, average 1.5). Choline-PET/CT outperformed conventional modalities across sensitivity, PPV, FNR, and accuracy. Among index operations, Choline-PET/CT had significantly higher sensitivity than conventional modalities (100% vs 27% for ultrasound, 30% for parathyroid scan, 29% for 4D-CT; p values ≤0.01). This was also true in re-operations (95% for Choline-PET/CT vs 13% for ultrasound, 30% for parathyroid scan, 32% for 4D-CT; p values <0.01). Conclusion: C11 choline-PET/CT is a valuable imaging modality in the re-operative setting and demonstrates utility for index operations. It provides localization when other modalities fail and allows for a high surgical cure rate. Further investigation into its utility as a primary imaging modality is warranted. Presentation: Monday, July 14, 2025

Abstract Disclosure: A. Ahmed: None. R. Kaddoura: None. T. Almas: None. N. Anavekar: None. Background: There is a recent interest focused on the use of glucagon-like peptide 1 (GLP-1) agonists, which are primarily used for diabetes and weight management, as a potential therapeutic approach for heart failure with persevered ejection fraction (HFpEF). We aim to evaluate the effects of GLP-1 agonists versus placebo on hospitalization rates, functional capacity, and cardiometabolic parameters in patients with HFpEF and obesity. Methods: We performed a systematic review and meta-analysis according to Cochrane handbook for systematic reviews and the preferred reporting items for systematic reviews and meta-analysis. We systematically reviewed three databases: PubMed, Embase, and Scopus, from inception to June 23rd, 2024, to investigate the comparative outcomes between GLP-1 agonist and placebo. Results: We identified 453 articles that were screened at the title and abstract level. We retrieved 14 citations and reviewed them in detail, among which two articles were eligible to be pooled. Hospitalization rates for heart failure were significantly reduced by 71 % (OR 0. 29 95 % CI: 0. 14-0. 58 p=0. 0005 I²=0 %), with GLP-1 agonist indicating a significant impact on lowering the cost of hospital admissions. Furthermore, GLP1 agonists significantly decreased body weight (MD -5. 64 kg 95 % CI: -11. 03 to -0. 25 p=0. 0404 I²=99 and waist circumference (MD -7. 09 cm 95 % CI: -8. 05 to -6. 14 p0. 0001 I²=76 %) demonstrating the positive effects of GLP-1 agonists on body composition. Improvements in functional capacity were evidenced by an increase in the 6-MWD (MD 15.10 m, 95% CI: 14.87-15.34, p<0.0001; I²=0%) (Fig 1 panel D). However, changes in systolic blood pressure were not statistically significant (MD -1.30 mmHg, 95% CI: -4.13 to 1.52, p=0.3660; I²=90%). Conclusion: GLP-1 agonists significantly reduce hospitalization rates and improve weight management and functional capacity in patients with HFpEF. However, further studies are warranted to consolidate these findings, explore the long-term cardiovascular outcomes, and address the cost-effectiveness of GLP-1 agonists. Presentation: Sunday, July 13, 2025

Abstract Disclosure: I. Bancos: AstraZeneca. A. Ben-Shlomo: AstraZeneca. O. Hamidi: Recordati Rare Diseases, Neurocrine Biosciences, Corcept Therapeutics, Crinetics, Camurus, Xeris. A. Hamrahian: AstraZeneca. W. Huang: None. L.S. Kirschner: Corcept Therapeutics, AstraZeneca, Crinetics, Sparrow Pharma, Spruce Biosciences. R. Sam: AstraZeneca. A.F. Turcu: AstraZeneca. A. Lihn: AstraZeneca. A. Mallappa: AstraZeneca. S. Perl: AstraZeneca. B. Tuyishimire: AstraZeneca. M.J. Brown: GlaxoSmithKline, Pfizer, Inc., Bristol-Myers Squibb, AstraZeneca. Introduction: Mineralocorticoid receptor antagonist (MRA) treatment for primary aldosteronism (PA) has limited efficacy in some patients. Highly selective, competitive aldosterone synthase inhibitors (ASIs) offer an alternative therapeutic approach. SPARK (NCT04605549) was a Phase 2, open-label, multicenter trial of the ASI baxdrostat in patients with PA. Methods: Eligibility entailed: aged ≥18 years; diagnosis of PA; willingness to discontinue MRA up to 4 weeks before baxdrostat initiation; and systolic blood pressure (SBP) rise ≥20 mmHg or SBP ≥160 mmHg after discontinuation of MRA, or SBP ≥150 mmHg for patients with newly diagnosed PA who had not taken MRAs in the past 12 weeks. Patients entered a 12-week treatment period (Part 1) of once daily baxdrostat 2 mg, up-titrated to 4 mg or 8 mg at week (W) 4 or W8, respectively, if there was no significant risk of hypotension. Baxdrostat could be down-titrated to 2 mg or continued at 4 mg as needed. After W12, patients could continue baxdrostat up to W72 (Part 2) with doses at investigators’ discretion. Primary endpoints were safety, tolerability and change from baseline in mean seated SBP at W12. Results: Fifteen patients enrolled and completed Part 1; 14 patients continued to Part 2. Median (range) age was 54 (32, 75) years, 67% of patients were male, 47% were White, and median (range) body mass index was 32.0 (24.4, 41.4) kg/m2. At baseline, plasma renin activity (PRA) was <1 ng/mL/h in 12/15 (80%) patients, and 8/15 (53%) patients had hypokalemia (serum potassium <3.5 mmol/L). Mean (range) baseline SBP was 151.5 (130, 174) mmHg; diastolic BP (DBP) was 90.3 (74, 103) mmHg. At W12, mean (range) SBP change from baseline was –29.5 (–47, –12), –24.4 (–31, –17), and –23.9 (–47, –8) mmHg for patients on baxdrostat 2 mg (n=2), 4 mg (n=5), and 8 mg (n=7), respectively; DBP change was –8.0 (–14, –2), –10.4 (–20, 0), and –11.6 (–25, 7) mmHg, respectively. Overall, 11/15 (73%) patients achieved BP <140/90 mmHg and 6/15 (40%) achieved BP <130/80 mmHg at W12; reduced BP persisted in Part 2. No deaths were reported. Nine out of 15 (60%) patients had a treatment-emergent adverse event (TEAE) during W4–W12 of Part 1 (all mild/moderate), including 1/15 (7%) patient with hyperkalemia; no serious TEAEs were reported. In Part 2, 14/14 (100%) patients had a TEAE (most mild/moderate), including 5/14 (36%) patients with hyperkalemia; one serious TEAE of hyperkalemia was reported. Mean (standard deviation, SD) serum potassium levels increased from 3.9 (0.6) mEq/L at baseline to 4.7 (0.5) mEq/L at W12. Mean (SD) 24-h urine aldosterone excretion at baseline and W12 were 30.3 (17.5) and 3.2 (2.7) µg/day, respectively. At W12, 7/15 (47%) patients had achieved unsuppressed PRA (≥1.0 ng/mL/h). Conclusions: Baxdrostat, an ASI, was well tolerated and led to reduced BP and unsuppressed renin in patients with PA. Inhibiting aldosterone synthase may be an alternative to MRAs for treating PA. Presentation: Sunday, July 13, 2025

Abstract Disclosure: R.J. Auchus: Has been involved in contracted research with companies such as Neurocrine Biosciences/Neurocrine UK, LTD, Spruce Biosciences, Corcept Therapeutics, Crinetics Pharmaceuticals, Recordati Rare Diseases, Adrenas Therapeutics, and Mineralys Pharmaceuticals, Served as consultant for organizations like Quest Diagnostics, Corcept Therapeutics, Xeris Pharmaceuticals, Crinetics Pharmaceuticals, Novo Nordisk, Neurocrine Biosciences/Neurocrine UK, LTD, Recordati Rare Diseases, H Lundbeck A/S, Sparrow Pharmaceuticals, Astellas Pharmaceuticals, and Acerand Therapeutics. O. Hamidi: Advisory board member for Neurocrine Biosciences, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals, Inc, Camurus, Xeris Pharmaceuticals, Inc, Educational speaking engagement with Recordati Rare Diseases. I. Bancos: None. K. Saag: Recieved grants or contracts from Amgen, Arthrosi, Horizon, LG Pharma, Radius, and Olatec, Received consulting fees from Amgen, Anthrosi, Atom Bioscience, Horizon, LG Pharma, Angitia, and Gruenthal. H. Falhammar: None. U. Srirangalingam: Consulting fees from Crinetics Pharmaceuticals, Diurnal Ltd and H Lundbeck A/S. M. Calanchini: None. E. Jen: Full-time employee of Neurocrine Biosciences, Inc. 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: Crinecerfont, a corticotropin releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to glucocorticoid (GC) replacement to control androgens in patients with classic congenital adrenal hyperplasia (CAH). In the Phase 3 CAHtalyst™ Adult study (NCT04490915), crinecerfont (100 mg BID) significantly reduced adrenal androgens, enabling substantial GC dose reductions from Day 1 baseline (BL) at the end of double-blind placebo-controlled (DBPC) treatment at Week 24, with a least-squares (LS) mean percent change of -27.3% vs. -10.3% for placebo (LS mean difference [LSMD] -17.0%, P<0.0001). At the end of open-label (OL) treatment at Month 12, mean percent decreases from BL in GC dose were -24.6% in participants who continued on crinecerfont (CFT/CFT) and -29.7% in those who switched from placebo (PBO/CFT). Objective: To evaluate clinical outcomes in adults with CAH who received up to 1 year of crinecerfont, in the context of substantial GC dose reductions. Methods: Outcomes related to excess adrenocorticotropic hormone (ACTH)/androgens (e.g., hirsutism in female participants) and GC exposure (e.g., body mass index [BMI], insulin resistance, hyperlipidemia) were analyzed at the end of DBPC treatment (Week 24) and the end of OL treatment (Month 12). DBPC outcomes with P-values are presented as LS mean changes with LSMD. Results: In female participants, mean hirsutism visual analog scale scores (out of 0 [no symptoms] to 100 [very severe symptoms]) were 40.6 (crinecerfont) and 37.4 (placebo) at BL. Changes from BL at end of DBPC (Week 24) and OL (Month 12) were: Week 24 (-9.8 for crinecerfont [n=58] vs -2.8 placebo [n=27], LSMD -7.0, P=0.1564); Month 12 (-11.5 CFT/CFT [n=56], -12.9 PBO/CFT [n=27]). Mean BMI at BL was 30.1 kg/m2 (crinecerfont) and 29.0 kg/m2 (placebo). Changes from BL were: at Week 24 (-0.4 vs. -0.02 for crinecerfont [n=118] vs. placebo [n=57], LSMD -0.40, P=0.1068); at Month 12 (-0.8 CFT/CFT [n=114], -0.4 PBO/CFT [n=56]). Mean homeostatic model assessment of insulin resistance values were high at BL (crinecerfont 3.2, placebo 3.0). Changes from BL were: at Week 24 (-0.6 vs. -0.4 for crinecerfont [n=61] vs placebo [n=29], LSMD -0.29, P=0.3454); at Month 12 (-0.5 CFT/CFT [n=107], -0.9 PBO/CFT [n=54]). Mean values for cholesterol (total, LDL, and HDL) and triglycerides were within normal range or near optimal at BL and remained stable. Conclusion: Adults with CAH who received up to 1 year of crinecerfont continued to show improvements in BMI and insulin resistance, as expected with lower GC doses. Moreover, despite substantial GC dose reductions, hirsutism in female participants improved with crinecerfont. Given the known adverse effects of ACTH/androgen excess and chronic supraphysiologic GC exposure, these results represent a promising therapeutic advancement in CAH. Presentation: Sunday, July 13, 2025

Abstract Disclosure: M. Fleseriu: None. C.P. Badiu: None. I. Bancos: None. E.B. Geer: None. M. Orbetzova: None. J.M. Silverstein: None. I. Uzunova: None. K.C. Yuen: None. T.K. Marmon: None. D.A. Katz: None. F.S. Czerwiec: None. Introduction: 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) regulates exposures of intracellular receptors to active glucocorticoids. HSD-1 deficiency suppresses a Cushing syndrome (CS) phenotype despite presence of hypercortisolism.1-3 Treatment with clofutriben (C), a potent and specific inhibitor of HSD-1, might improve CS comorbidities by decreasing intracellular cortisol. Methods: Seventeen adults with CS (16 pituitary, 1 ectopic), and type 2 diabetes (T2D), impaired glucose tolerance (IGT), hypertension (HTN), hyperlipidemia, or osteopenia were randomized to a total of 12 weeks of oral C 6mg/d and 12 weeks of matching placebo (P) in 2 blinded sequences (PCCP, CCPP; “P” or “C” representing 6-week periods). Patients were offered open-label C treatment on completion. Primary endpoint was urinary ratio of cortisol and cortisone metabolites at Week 6 (hepatocellular HSD-1 activity biomarker). Key exploratory endpoints (and applicable population) at Week 6 were OGTT-AUCglucose decrease 25% (IGT/T2D), HbA1c decrease ≥ 0.5% (T2D), systolic blood pressure decrease ≥ 5mmHg or decreased treatment (HTN), and normalization of urinary free cortisol (baseline >1.5xULN). Results: Mean baseline HSD-1 ratio was 1.95 +/- 0.171. At Week 6, mean ratio was 0.21 +/- 0.091 with C and 2.01 +/- 0.263 with P. More patients responded at Week 6 to C on OGTT-AUCglucose (4/8 v 0/5), HbA1c (4/5 v 0/4), systolic blood pressure (5/7 v 2/4), and urinary free cortisol (3/8 v 0/6). Concomitant medications for T2D were reduced in 4 C-treated but increased in 2 P-treated patients. For HTN there were also 4 reductions for C-treated and 1 increase for P-treated patients. One patient succumbed to ectopic Cushing’s due to cervical carcinoma after discontinuing the trial. Four patients discontinued for reasons other than an adverse event (AE). One serious AE of vomiting (possible glucocorticoid withdrawal syndrome per investigator) led to temporary drug interruption. Common AEs (≥ 3 patients) included Arthralgia, Fatigue, Headache, and Nausea, but only Headache was more common in C during the P-controlled period. There was no evidence of clinical or biochemical (defined by low morning plasma cortisol) adrenal insufficiency. All 13 patients who completed elected to enter the open-label extension (current treatment duration 3-15 months). Conclusions: Clofutriben decreased hepatic HSD-1 activity adequately to confer clinical benefit while maintaining safety and overall tolerability. These limited data support clofutriben’s potential for clinical improvement without adrenal insufficiency. References: 1Tomlinson JW 2002; 2Arai H 2008; 3Weber RJ 2024 Presentation: Sunday, July 13, 2025

Abstract Disclosure: D.S. Ali: None. Z. Chung: None. L. Kamel: None. S. Björnsdottir: Shire. B.L. Clarke: Shire, Takeda, Ascendis, Calcilytix. S. Hahner: None. L.C. Hofbauer: Amgen Inc, Ascendis, UCB, Ascendis, Amolyte. P. Houillier: None. S.W. Ing: Amgen Inc, Radius Health, Inc, Takeda, AscendAlexion, Amolyt, Ascendis, Calcilytix, Kyowa Kirin. M.A. Levine: Takeda, Amolyt, Calcilytix. M. Mannstadt: Takeda, Amolyt, Calcilytix. L. Rejnmark: Takeda, Amolyt, Ascendis, Calcilytix. D.M. Shoback: Amolyt, Ascendis, member of the advisory board (PARADIGHM). M. Brandi: Takeda, Eli Lilly & Company, Calcilytix, Kyowa Kirin, UCB, Abiogen, Alexion, Amolyt, Amorphical, Bruno Farmaceutici, CoGeDi, Echolight. A.A. Khan: Takeda, Amgen Inc, Alexion, Ascendis, Amolyt, Calcilytix. Background: Hypoparathyroidism (HypoPT) is a rare endocrine disorder that requires close evaluation and follow up during pregnancy to minimize maternal and fetal complications. The primary objectives of this study are to evaluate the use of rhPTH (1-84) during pregnancy by analyzing data from the PARADIGHM disease registry, and to compare maternal and neonatal outcomes among patients who continued PTH therapy during pregnancy versus those on conventional therapy (CT). Methods: We performed a retrospective analysis of data in the PARADIGHM registry. Maternal and neonatal outcomes in women treated with rhPTH (1-84) were compared to women who received CT. Results: We analyzed 39 pregnancies of 32 women. Of those, 4 women (6 pregnancies) used rhPTH (1-84) either before or during pregnancy and 28 women (33 pregnancies) continued CT during pregnancy. The mean (SD) maternal age at enrollment was 31.7 (5.6) years. Postsurgical HypoPT was the most common etiology (68.8%). The mean gestational age at delivery was 36 (2.4) weeks (PTH-treated) vs 38.3 (3.3) weeks (CT) (p=0.162). Preterm delivery rates were higher in the PTH-treated group (50% vs. 27%, p=0.591), but this was not statistically significant. Two women had pre-eclampsia, one in each group (PTH-treated and CT). In the PTH-treated group, one pregnancy resulted in a stillbirth, and one infant was born with congenital anomalies (16.7% each). Conclusions: The safety of rhPTH (1-84) use in pregnancy cannot be determined at this time. The PTH-treated group exhibited trends towards higher rates of preterm delivery, but the rates of stillbirth, and congenital anomalies were low and comparable in both groups of women. Larger studies are necessary to determine the optimal approach to manage women with HypoPT during pregnancy. Presentation: Sunday, July 13, 2025