Citations

Abstract Context Adult growth hormone (GH) deficiency (GHD) is characterized by metabolic abnormalities caused by insufficient GH production. Lonapegsomatropin, a prodrug administered once weekly, was designed to provide sustained release of unmodified somatropin to reduce the burden of daily somatropin injections. Objective This work aimed to evaluate the efficacy and safety of lonapegsomatropin vs placebo as treatment for adults with GHD. Methods The foresiGHt trial was a multicenter, randomized, parallel-arm, placebo-controlled (double-blind) and active-controlled (open-label) trial (NCT04615273) conducted at 116 centers in North America, Europe, and Asia-Pacific. The trial randomly assigned and dosed 259 adults with GHD. Participants were randomly assigned 1:1:1 to receive once-weekly lonapegsomatropin, once-weekly placebo, or daily somatropin for 38 weeks. The primary efficacy end point was change from baseline in trunk percent fat at week 38. Secondary efficacy end points included change from baseline in trunk fat mass and total body lean mass. Results At week 38, lonapegsomatropin significantly reduced trunk percent fat (−1.68% vs +0.37%; least squares [LS] mean difference −2.04%; P < .001), increased total body lean mass (+1.60 kg vs −0.11 kg; LS mean difference 1.70 kg; P < .0001), and reduced trunk fat mass (−0.48 kg vs +0.22 kg; LS mean difference −0.70 kg; P = .0053) vs placebo. The safety and tolerability profile of lonapegsomatropin was comparable to somatropin. Conclusion The foresiGHt trial met its primary efficacy end point by demonstrating superiority of lonapegsomatropin vs placebo with similar safety and tolerability, supporting its potential as a once-weekly treatment option for adults with GHD.

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 Craniopharyngiomas are rare parasellar tumors, and papillary craniopharyngiomas (PCPs) represent 8 to 20% of cases. Interim analysis of retrospective data collected from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). Fourteen U.S.-based academic skull base centers between 2011 and 2023. Patients with PCPs. Demographic, imaging, surgical, and outcome variables. Ninety-nine patients with PCPs were included. The mean age was 51.8 ± 14.7, and 57.6% were male. Most tumors showed mixed cystic/solid components (67.5%), were transinfundibular (50.0%), and were treated with an endoscopic endonasal approach (74.5%), with 51.1% demonstrating gross total resection (GTR). Pituitary stalk was preserved in 51.9%. Permanent arginine vasopressin deficiency was seen in 67.1% and was associated with pituitary stalk sacrifice (p = 0.003). Cerebrospinal fluid leak was the most common nonendocrine postsurgical, 30-day complication (9.1%), reason for return to the operating room (3.1%), and reason for 90-day readmission (8.1%). Most patients (63.9%) received no adjuvant therapy; GTR was associated with decreased radiotherapy use (p = 0.0001). BRAFV600E mutation was detected in 64/69 tumors tested, although only one patient was treated with a BRAF inhibitor. A mean follow-up of 12.3 ± 14.6 months was seen for the group. RAPID consortium enabled the largest real-world clinical information dataset for PCPs. Early findings support that GTR and stalk preservation are important to outcomes. Iterative analysis and discussion of data led to the generation of a framework for future studies to fully leverage the capabilities of multicenter registries.

Abstract Introduction Endogenous Cushing's syndrome (CS) is a rare endocrine disorder that chronically exposes patients to supraphysiological cortisol levels. Primary therapy for CS consists of surgery. Medical therapies are also considered for many patients with CS, including those who are not surgical candidates or have persistent or recurrent hypercortisolism after surgery. Osilodrostat, an adrenal steroidogenesis inhibitor, demonstrated sustained efficacy and safety in phase 3 clinical trials and is currently approved to treat endogenous CS in Europe and the United States. Because of limited clinical experience, questions remain about how to individualize osilodrostat treatment for different clinical scenarios and special populations. Additional guidance from experts based on clinical study and real-world experiences with osilodrostat is needed. Methods A modified Delphi consensus panel study was conducted consisting of 13 specialists from high-volume endocrinology centers with experience prescribing osilodrostat. Advisors participated in 3 consensus rounds (2 anonymous surveys, 1 virtual workshop) over approximately 10 months to provide guidance and recommendations on optimal osilodrostat use. Results Over 2 surveys and a 2-hour virtual workshop, 26 statements related to osilodrostat achieved consensus among Delphi panelists and 5 were excluded. Topics included patient preparation before osilodrostat initiation, baseline testing, dosing at onset and during treatment, managing dose adjustments, monitoring during dose titration, and treatment alterations for planned and unexpected clinical events. Conclusion Treatment guidance and recommendations for osilodrostat use were obtained using the Delphi method. These statements are intended to provide physicians with education and guidance on using osilodrostat to optimally treat patients with CS.

OBJECTIVE Reports of surgical outcomes for Cushing’s disease are mostly limited to single-center experiences by expert surgeons. Therefore, no generalizable surgical outcome metrics for endoscopic endonasal Cushing’s disease surgery are available for practitioners to guide quality-improvement efforts. This is potentially problematic, given the high morbidity and excess mortality observed in patients who do not achieve remission. This study proposes a bundle of evidence-based metrics for low-risk patients with Cushing’s disease, for whom optimal outcomes would be expected, that focus on the cost efficiency of care and surgical outcomes from multicenter collaboration of US pituitary centers. METHODS The steering committee of the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) consortium proposed the metrics based on available data from 12 US pituitary centers. A benchmarking population of low-risk patients undergoing first-time surgery was identified. Patient characteristics and outcomes were aggregated and analyzed by a data coordinating center. Metrics were reported using 2 approaches. RESULTS A total of 431 patients from 12 centers who underwent primary endoscopic transsphenoidal surgery from January 1, 2006, to December 31, 2022, were included. There were 227 patients in the low-risk cohort (age < 70 years, BMI < 50, microadenoma, and Knosp grade 0–2). For the cost-efficiency metrics, the mean (SD) length of stay was 3.8 (4.8) midnights, and the percentage of patients readmitted was 11.1%. The rate of disposition to a skilled nursing facility was 2.2%. For surgical outcomes, the rate of postoperative CSF leakage was 1.3%, and the rate of 1-year sustained surgical remission was 81.2%. The rates of permanent and temporary arginine vasopressin deficiencies were 1.8% and 11.9%, respectively. The 75th percentile performance by center was 3.0 midnights for length of stay, 6.3% for 90-day unplanned readmission, < 1% for disposition to a skilled nursing facility, < 1% for CSF leakage, and 92.2% for 1-year sustained remission. The 75th percentile was < 1% for both permanent and temporary arginine vasopressin deficiencies. CONCLUSIONS An evidence-based bundle of metrics in a Cushing’s disease patient population at low risk who underwent first-time endoscopic pituitary surgery is proposed. Surgeons can use these metrics to assess and improve the quality of their clinical pathways.

Abstract Purpose: Craniopharyngiomas are rare parasellar tumors, and papillary craniopharyngiomas (PCP) represent 8-20% of cases. We assessed surgical outcomes of these very rare tumors among patients treated in the last decade. Methods: Retrospective data from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) were used to evaluate patients with PCP treated between 2011 and 2023 at 14 US-based academic skull base centers. Demographic, imaging, surgical, and outcome variables were analyzed. Results: Ninety-nine patients with PCP were included. Mean age was 51.8±14.7 and 57.6% were male. Most tumors showed mixed cystic/solid components (67.5%), were trans-infundibular (50.0%), and were treated endoscopically (74.5%), with 51.1% demonstrating gross total resection (GTR). Pituitary stalk was preserved in 51.9%. Permanent arginine vasopressin deficiency was seen in 68.8% and was associated with pituitary stalk sacrifice (p=0.02). Cerebrospinal fluid leak was the most common nonendocrine postsurgical, 30-day complication (9.1%), reason for return to the operating room (3.1%), and reason for 90-day readmission (8.1%). Return to the operating room was associated with discharge to a skilled nursing or rehabilitation facility (p=0.0001). Most patients (63.9%) received no adjuvant therapy; GTR was associated with decreased radiotherapy use (p=0.0001). BRAFV600E mutation was detected in 64/69 tumors tested, although only 1 patient was treated with a BRAF inhibitor. Conclusion: To our knowledge, the RAPID consortium enabled the largest real-world clinical information dataset for PCP. Our data can be used as a benchmark for short-term surgical outcomes. Longer-term follow-up studies are needed to understand how to optimize outcomes from each treatment modality.