First Oral Therapy for Rare Adrenal Gland Tumors Gets Green Light From FDA

Posted on May 17, 2025 by MaryO
FDA approval for Welireg.

The FDA has expanded the approval of belzutifanopens in a new tab or window (Welireg) to include certain types of pheochromocytoma or paraganglioma (PPGL) in adults and children.

The action establishes belzutifan as the only approved oral therapy for PPGL. The approval stipulates use in adults and children 12 years or older with locally advanced, unresectable, or metastatic PPGL.

Support for the approval came from the LITESPARK-015opens in a new tab or window multi-cohort trial. Cohort A1 involved 72 patients with locally advanced or metastatic PPGL not amenable to surgery or curative treatment. Patients with concomitant hypertension adequately managed with blood pressure medication were required to have stable therapy for at least 2 weeks prior to enrollment.

The primary outcome was objective response rate (ORR). Secondary outcomes included duration of response (DOR) and number of patients with at least a 50% dose reduction for one or more antihypertensive medications for at least 6 months.

The results showed an ORR of 26% and a median DOR of 20.4 months. Additionally, 19 of 60 patients on baseline antihypertensive medications met the prespecified dose-reduction target.

Adverse reactions occurring in ≥25% of patients included anemia; fatigue; musculoskeletal pain; increased liver enzymes, calcium, potassium, and alkaline phosphatase; decreased lymphocytes and leukocytes; dyspnea; headache; dizziness; and nausea.

PPGLs comprise a group of rare neuroendocrine tumorsopens in a new tab or window that have an incidence of approximately 0.57 per 100,000 person-years. The tumors occur in 0.1% t0 0.6% of patients with hypertension and account for about 5% of adrenal incidentalomas.

A hypoxia-inducible factor-2α inhibitor, belzutifan previously received approval for advanced renal cell carcinomaopens in a new tab or window and certain subtypes of von Hippel-Lindau diseaseopens in a new tab or window.

Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow 

From https://www.medpagetoday.com/hematologyoncology/othercancers/115582

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Mortality in Cushing’s Syndrome: Declining Over Two Decades but Remaining Higher Than the General Population

Posted on April 18, 2025 by MaryO

Abstract

Objective

Patients with endogenous Cushing’s syndrome (CS) have elevated mortality, particularly during active disease. A recent meta-analysis reported reduced mortality rates after 2000 in adrenal CS and Cushing disease (CD), though many studies lacked population-matched controls.

Methods Nationwide retrospective study (2000–2023) in Israel using the Clalit Health Services database to assess all-cause mortality in patients with endogenous CS matched 1:5 with controls by age, sex, socioeconomic-status, and BMI. Primary outcome was all-cause mortality. Secondary outcomes included cause-specific mortality, impact of hypercortisolism remission, disease source, and mortality risk factors.

Results The cohort included 609 cases with CS (mean age 48.1±17.2 years; 65.0% women) and 3,018 matched controls (47.9±17.2 years; 65.4% women). Over a median follow-up of 16 years, 133 cases (21.8%) and 472 controls (15.6%) died (HR=1.44, 95% CI, 1.19–1.75). Both patients with CD (HR=1.73, 95% CI, 1.27–2.36) and adrenal CS (HR=1.31, 95% CI, 1.00–1.81) had increased mortality risk. Patients without remission within 2 years had a higher mortality risk than those achieving remission (HR=1.44, 95% CI, 1.00–2.17). Mortality was similar for CD and adrenal CS (HR=0.83, 95% CI, 0.56–1.24). Older age, male gender, and prior malignancy were independent risk factors for mortality.

Conclusion This is the largest national cohort study on mortality risk in CS over the past two decades, showing a significantly higher risk compared to matched controls in a homogeneous database. While etiology had no impact, remission significantly affected mortality, highlighting the importance of disease control for long-term survival.

Request the full article at https://www.researchgate.net/publication/390437820_Mortality_in_Cushing’s_Syndrome_Declining_Over_Two_Decades_but_Remaining_Higher_Than_the_General_Population

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Impact of Remission Status in Endogenous Cushing’s Syndrome on Cancer Incidence

Posted on March 4, 2025 by MaryO

Abstract

Objective
Endogenous Cushing’s syndrome (CS) has been linked with an increased risk of cancer. We aimed to evaluate the association between cancer risk and disease remission post-surgery in adrenal CS and Cushing’s disease (CD).
Design
A nationwide retrospective matched-cohort study of patients with CS diagnosed between 2000-2023 in Israel, using Clalit Health Services’ database. Methods Patients with CS were matched 1:5 with controls by age, sex, socioeconomic status, and BMI. Remission status post-surgery was assessed within two years after the diagnosis of CS. The outcome measured was time to first diagnosis of malignancy, at least three years post-CS diagnosis, excluding those who died or developed cancer earlier. Malignancy risk, stratified by remission status, was evaluated using Cox proportional hazards with death as a competing event.
Results
The cohort comprised 388 cases and 1,862 controls [mean age at diagnosis, 47.4±16.8 years; 1,534 (68.2%) women]. Among patients with CD, those who did not achieve remission within 2 years post diagnosis (n=69) had a higher risk of malignancy compared to those who achieved remission (n=99) (HR 3.89, 95% CI 1.41-10.75). Cancer risk in patients with CD who achieved remission was similar to that of the controls (HR 0.58, 95% CI 0.23-1.47). In patients with adrenal CS, the risk of cancer was comparable between those who did not achieve early remission (n=39) and those who did (n=113) (HR 1.68, 95% CI 0.83-3.40).
Conclusion
Though cancer risk is higher in both CD and adrenal CS, we have shown that achieving surgical remission within 2 years may attenuate cancer risk in patients with CD, but not in those with adrenal CS.

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Oncocytic Pituicytoma in a Patient with Cushing’s Disease

Posted on February 20, 2025 by MaryO

The final, formatted version of the article will be published soon.

1) Background: Posterior pituitary tumors (PPTs) are extremely rare, with fewer than 400 cases reported to date. In 2022, the WHO classified four types of tumors originating from the posterior pituitary: traditional pituicytoma, oncocytic pituicytoma, granular pituicytoma, and ependymal pituicytoma. To our knowledge, only one subject with coexistence of Cushing’s disease and oncocytic pituicytoma (spindle cell oncocytoma) has been reported, but the clinical features of this patient were not described in detail.

2) Case presentation: We presented a case of a patient with Cushing’s syndrome and a pituitary mass. Transsphenoidal surgery was performed, and pathologic examination revealed two distinct tumors: a corticotroph adenoma with a diameter of less than 2mm and a larger oncocytic pituicytoma. Post-surgery serum cortisol was 51 nmol/L, indicating complete remission. Corticotroph adenoma or corticotroph hyperplasia were identified after surgery in less than half of the subjects with Cushing’s disease and PPT. (3)

Conclusions: Our study indicates that Cushing’s disease in patients with PPT may be caused by the existence of collision lesions, with corticotroph adenoma or hyperplasia being difficult to detect due to their small dimensions.

Keywords: Cushing’s disease, oncocytic pituicytoma, Spindle cell oncocytoma, pituitary adenoma, Posterior pituitary tumors

Received: 27 Aug 2024; Accepted: 17 Feb 2025.

Copyright: © 2025 Li, Chen, Tan, Yu, Tang, Cai and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Huiwen Tan, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
Ying Tang, Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Bowen Cai, Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Jianwei Li, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

 

From https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1487120/abstract

 

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Corcept’s relacorilant GRADIENT trial misses primary endpoint

Posted on November 6, 2024 by MaryO

Corcept Therapeutics has shared some results from its Phase III GRADIENT trial for relacorilant – its experimental treatment for Cushing’s syndrome caused by adrenal gland pathology.

The trial will be used alongside data from the earlier GRACE trial to support the company’s new drug application (NDA) submission this quarter. However, it missed its primary endpoint.

The complete results of the company’s GRADIENT trial will be presented at a medical conference next year, but current results – released on 30 October – demonstrate that there was no statistically significant difference in hypertension in relacorilant and placebo patients.

The randomised double-blind trial included 137 patients across sites in the US, Europe and Israel. Over 22 weeks, half of the patients received relacorilant while the other half received a placebo.

The trial’s primary endpoint was the improvement in systolic blood pressure (SBP) compared to placebo. Its secondary endpoints were concerned with hyperglycemia, weight and body composition.

Mean SBP saw a reduction of 6.6 mm Hg in relacorilant patients compared to baseline. This is in contrast to a reduction of 2.1 mm Hg in placebo patients. The difference between these results was not statistically significant.

However, Corcept’s GRADIENT trial did meet some secondary endpoints and was well-tolerated. Patients taking relacorilant exhibited clinically meaningful and statistically significant improvements in hypertension, hyperglycemia, weight and body composition compared to baseline. In contrast, placebo patients did not.

Cushing’s syndrome is caused by an excess of cortisol and primarily affects those using steroid medications, which contain a synthetic version of the hormone. The condition is characterised by an increase of fat (particularly on the neck and shoulders), a change in face shape, stretch marks and skin which bruises easily. Cushing’s syndrome can also cause hypertension.

Corcept Therapeutics also shared that relacorilant was well-tolerated in the GRADIENT trial. It reported that there were no cases of relacorilant-induced hypokalemia, endometrial hypertrophy or related vaginal bleeding, adrenal insufficiency or QT prolongation.

The NDA submission for relacorilant for Cushing’s syndrome is expected this quarter. The GRADIENT trial will support results from the company’s GRACE trial, which were shared in June. The GRACE trial included 152 patients and met its primary endpoint of loss of hypertension control in the randomised-withdrawal phase.

Considering the results of the GRADIENT trial, Corcept Therapeutics’ chief development officer Bill Guyer said: “GRADIENT’s positive results in patients with Cushing’s syndrome confirm relacorilant’s promise as a significant medical advancement for the treatment of this deadly disease. As was true in the GRACE study, patients in GRADIENT who received relacorilant experienced clinically meaningful improvements in a broad range of hypercortisolism signs and symptoms, without suffering some of the serious adverse effects that can arise in patients taking currently approved treatments.

“These data will be a powerful addition to relacorilant’s NDA, which we plan to submit by year-end.”

https://www.clinicaltrialsarena.com/news/corcepts-relacorilant-gradient-trial-misses-primary-endpoint/?cf-view

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