Introduction: The Burden of Endogenous Hypercortisolism
Endogenous hypercortisolism, commonly known as Cushing’s syndrome, is a rare but devastating endocrine disorder characterized by chronic overexposure to cortisol. Whether arising from an ACTH-secreting pituitary adenoma (Cushing’s disease), ectopic ACTH production, or autonomous adrenal cortisol secretion, the multisystemic impact of hypercortisolism is profound. Patients frequently suffer from central obesity, proximal muscle weakness, skin fragility, and severe neuropsychiatric disturbances. However, the primary drivers of increased mortality and cardiovascular risk in this population are metabolic: treatment-resistant hypertension and impaired glucose tolerance or diabetes mellitus.
Managing Cushing’s syndrome remains a significant clinical challenge, particularly when surgical intervention—the first-line treatment—is unsuccessful, contraindicated, or not curative. Pharmacological options have historically focused on inhibiting steroidogenesis (e.g., ketoconazole, metyrapone) or blocking the glucocorticoid receptor (GR). While effective, existing GR antagonists like mifepristone are non-selective, also blocking the progesterone receptor (PR). This lack of selectivity leads to significant adverse effects, including endometrial thickening and vaginal bleeding in women, and the saturation of the mineralocorticoid receptor pathway, leading to severe hypokalemia. The GRACE study was designed to evaluate relacorilant, a selective GR modulator, as a next-generation therapeutic that addresses these unmet safety and efficacy needs.
Study Design and Methodology
The GRACE study (NCT03697109) was a multicentre, phase 3, double-blind, placebo-controlled, randomised-withdrawal trial conducted across 77 sites in 11 countries. This innovative trial design was specifically chosen to demonstrate the durability of the treatment effect in a rare disease population where large, long-term parallel-group studies are difficult to execute.
Patient Population and Inclusion Criteria
The study enrolled adults (aged 18–80 years) with confirmed endogenous hypercortisolism who also presented with clinical manifestations of the disease, specifically hypertension, hyperglycemia, or both. Participants were required to have at least two clinical signs of hypercortisolism. This ensured the study focused on patients with significant disease burden requiring systemic intervention.
Phases of the Trial
The study was divided into two distinct periods. First, an open-label phase lasted 22 weeks, during which all participants received relacorilant. The dose was carefully escalated from 100 mg up to a maximum of 400 mg once daily, based on individual patient tolerance and clinical response. Patients who met predefined response criteria regarding blood pressure or glucose metabolism at the end of this phase were then eligible for the second period.
The second period was a 12-week randomized-withdrawal phase. Responders were assigned in a 1:1 ratio to either continue their optimized dose of relacorilant (up to 400 mg) or switch to a matching placebo. Both investigators and participants remained masked to the treatment assignment during this phase to maintain the integrity of the efficacy data.
Primary and Secondary Endpoints
The primary outcome measure was the proportion of patients who experienced a loss of hypertension response during the randomized-withdrawal phase. Loss of response was defined by specific increases in systolic or diastolic blood pressure or the need for increased antihypertensive medication. Secondary endpoints included changes in glucose metabolism and overall safety and tolerability.
Key Findings: Efficacy in Hypertension and Metabolic Stability
Between October 2018 and April 2024, 404 patients were screened and 152 were enrolled. Of these, 95 completed the open-label phase, and 62 met the rigorous response criteria to enter the randomized-withdrawal phase. The results provided clear evidence of relacorilant’s ability to maintain clinical improvements.
Maintenance of Blood Pressure Control
In the randomized-withdrawal phase, relacorilant demonstrated statistically significant superiority over placebo in maintaining hypertension control. Among patients who had achieved a blood pressure response during the open-label phase, those switched to placebo were significantly more likely to lose that control. The proportion difference between the groups was 34%, with an odds ratio of 0.17 (95% CI 0.04–0.77; p=0.022). This finding confirms that the blood pressure improvements observed during the initial 22 weeks were directly attributable to relacorilant and not to a placebo effect or natural disease fluctuation.
Safety and Tolerability Profile
One of the most significant aspects of the GRACE trial was the safety profile of relacorilant. Because relacorilant is a selective modulator with no affinity for the progesterone receptor, the study observed no cases of vaginal bleeding associated with endometrial hypertrophy—a common and distressing side effect of mifepristone.
Furthermore, the selective nature of the drug meant there were no cases of drug-induced hypokalaemia. In traditional GR antagonism, the blockage of GR can lead to a compensatory increase in ACTH and cortisol. In the presence of non-selective drugs, this excess cortisol spills over to activate the mineralocorticoid receptor, causing potassium depletion. Relacorilant appears to avoid this pathway. Additionally, there were no reported cases of adrenal insufficiency, a critical safety concern in most Cushing’s syndrome therapies that lower or block cortisol activity. The most common adverse events reported were back pain, acne, and arthralgia, which were generally mild and distributed similarly between the relacorilant and placebo groups during the withdrawal phase.
Expert Commentary and Clinical Implications
The GRACE study represents a potential shift in the management of Cushing’s syndrome. From a mechanistic perspective, the selective modulation of the glucocorticoid receptor offers a surgical-like precision in pharmacological form. By competing with cortisol only at the GR, relacorilant mitigates the downstream effects of hypercortisolism—such as the activation of genes involved in gluconeogenesis and vasoconstriction—without interfering with other hormonal axes.
Addressing the Limitations of Current Therapy
For many years, clinicians have struggled with the trade-offs of medical therapy. Steroidogenesis inhibitors require frequent monitoring of serum cortisol to avoid adrenal crisis, and non-selective antagonists require close monitoring of potassium and pelvic ultrasounds in women. The GRACE data suggests that relacorilant could simplify the management of these patients, providing a more predictable safety profile. This is particularly relevant for patients with ACTH-dependent Cushing’s who are not candidates for surgery or who have failed radiotherapy.
Methodological Considerations
The use of a randomized-withdrawal design is particularly robust for establishing the efficacy of a drug in a chronic condition. By showing that withdrawing the drug leads to a return of symptoms (hypertension), the investigators have provided high-level evidence of a causal relationship between relacorilant and clinical improvement. However, it is important to note that the trial specifically looked at patients who were responders; future real-world data will be needed to further define the characteristics of patients most likely to benefit from this therapy.
Conclusion
The Phase 3 GRACE trial successfully met its primary endpoint, demonstrating that relacorilant is effective in maintaining blood pressure control in patients with endogenous hypercortisolism. The selective nature of this glucocorticoid receptor modulator provides a favorable safety profile, avoiding the progesterone-related and mineralocorticoid-related side effects that have historically limited the use of GR antagonists. As the medical community seeks better ways to manage the harmful and debilitating effects of Cushing’s syndrome, relacorilant emerges as a promising therapeutic option that balances efficacy with a refined safety profile.
Funding and Clinical Trial Information
This study was funded by Corcept Therapeutics. ClinicalTrials.gov Identifier: NCT03697109.
References
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