FDA Issues Complete Response Letter for Relacorilant for Hypercortisolism

Announced by parent company Corcept Therapeutics on December 31, 2025, the US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding relacorilant's New Drug Application (NDA) for hypercortisolism.1

"We are surprised and disappointed by this outcome," Joseph Belanoff, MD, chief executive officer of Corcept, said in a statement. "Our commitment to patients suffering from the effects of hypercortisolism is unwavering."1

The FDA acknowledged that Corcept's pivotal GRACE trial met its primary endpoint and that the company's GRADIENT trial provided confirming evidence. However, the FDA also determined that it was unable to determine a favorable benefit-risk assessment without additional evidence of effectiveness.1

Relacorilant is a selective cortisol modulator, designed to bind to glucocorticoid receptors without interacting with other hormone receptors. Corcept is currently investigating relacorilant in several different disorders, including ovarian and prostate cancer.2

The NDA submission was based on results from the pivotal GRACE trial and the phase 3 GRADIENT trial, as well as a phase 2 trial in hypercortisolism and a long-term extension. GRACE was a 2-part, phase 3, double-blind, placebo-controlled, randomized-withdrawal study examining the safety, efficacy, and pharmacokinetics of relacorilant in patients with endogenous hypercortisolism and concurrent type 2 diabetes (T2D) with impaired glucose tolerance and/or uncontrolled hypertension.2

The first phase of GRACE was an open-label period where patients with hypercortisolism and either hypertension, hyperglycemia, or both received relacorilant for 22 weeks. Investigators excluded patients with non-endogenous hypercortisolism, uncontrolled and clinically significant hypothyroidism or hyperthyroidism, poorly controlled hypertension, poorly controlled diabetes mellitus, or renal insufficiency.2,3

The second phase was a double-blind, randomized, withdrawal period, allowing investigators to measure blood pressure control maintenance. In this phase, patients who met response criteria were randomly assigned in a 1:1 ratio to either continue relacorilant or switch to placebo therapy for 12 weeks.2

Ultimately, investigators found that loss of blood pressure control was 83% less likely to occur in the relacorilant arm compared to placebo (odds ratio [OR], 0.17; P = .02), along with similar blood pressure trends favoring relacorilant over placebo in 24-hour systolic and diastolic blood pressure.3

GRADIENT was a randomized, double-blind, placebo-controlled study assessing the efficacy and safety of relacorilant to treat hypercortisolism in patients with cortisol-secreting adrenal adenoma or hyperplasia associated with diabetes mellitus/impaired glucose tolerance and/or uncontrolled systolic hypertension. Investigators included patients with a lack of cortisol suppression based on dexamethasone suppression testing, suppressed or low early-morning adrenocorticotropic hormone levels, and a radiologically confirmed adrenal lesion. Patients were excluded if they had severe uncontrolled hypertension, poorly controlled diabetes mellitus, type 1 diabetes, significantly abnormal liver test results, or uncontrolled hypo- or hyperthyroidism.4

Patients were randomly assigned in a 1:1 ratio to either oral relacorilant or placebo for 22 weeks. Primary outcomes included change in average 24-hour systolic blood pressure and the number of patients with ≥1 treatment-emergent adverse event. Secondary endpoints included change in average heart rate, average diastolic blood pressure, and area under the concentration-time curve of blood glucose, among others.4

Patients receiving relacorilant exhibited substantial and clinically significant improvements in mean systolic blood pressure at 22 weeks compared to baseline, while those receiving placebo saw no significant reduction. Additionally, 5 patients receiving placebo required rescue therapy, compared to 1 receiving relacorilant.5

"I am confident we will find a way to get relacorilant to the patients it could help," Belanoff said in the statement. "We will meet with the FDA as soon as possible to discuss the best path forward."1

References

1. Corcept Therapeutics. Corcept Receives Complete Response Letter for Relacorilant as a Treatment for Patients with Hypercortisolism. BusinessWire. December 31, 2025. Accessed December 31, 2025. https://www.businesswire.com/news/home/20251231309474/en/Corcept-Receives-Complete-Response-Letter-for-Relacorilant-as-a-Treatment-for-Patients-with-Hypercortisolism

2. Corcept Therapeutics. A Study of the Efficacy and Safety of Relacorilant in Patients With Endogenous Cushing Syndrome (GRACE). ClinicalTrials.gov Identifier: NCT03697109. Updated July 16, 2025. Accessed December 23, 2025. https://clinicaltrials.gov/study/NCT03697109

3. Campbell P. Full GRACE Results Shed Further Light on Effects of Relacorilant in Hypercortisolism. HCPLive. June 7, 2024. Accessed December 23, 2025. https://www.hcplive.com/view/full-grace-results-shed-further-light-on-effects-of-relacorilant-in-hypercortisolism

4. Corcept Therapeutics. A Study of the Efficacy and Safety of Relacorilant in Patients With Cortisol-Secreting Adrenal Adenomas (GRADIENT). ClinicalTrials.gov Identifier: NCT04308590. Updated September 4, 2025. Accessed December 23, 2025. https://clinicaltrials.gov/study/NCT04308590

5. Corcept Therapeutics. Corcept Therapeutics Announces Third Quarter Financial Results, Positive Results from Phase 3 GRADIENT Trial in Patients With Cushing’s Syndrome and Provides Corporate Update. October 30, 2024. Accessed December 23, 2025. https://ir.corcept.com/news-releases/news-release-details/corcept-therapeutics-announces-third-quarter-financial-results-3