RELACORILANT: A Ray of Hope for Endogenous Cushing’s Syndrome

By Donn Ronn Pagador, MD and Gretchen Ang-Manuel, MD
De La Salle University Medical Center

Medical treatment of Endogenous Cushing’s syndrome is limited.  The currently available medications often have undesirable side effects. For instance, Levoketoconazole, Osilodrostat, Pasireotide and Mifepristone can cause QTc prolongation increasing the risk for Torsades de pointes, ventricular fibrillation and sudden cardiac death. Also, mifepristone was seen to cause drug-induced vaginal bleeding.¹

Relacorilant is a highly-selective glucocorticoid receptor modulator that competitively antagonizes cortisol activity but without progesterone activity. In a dose-finding, open-label, phase 2 study done at 19 sites in the United States and Europe, Relacorilant was administered among adult patients (aged 18-80 years old) with established endogenous Cushing’s Syndrome requiring medical treatment (those for whom surgery or radiation is contraindicated or has been refused). Participants received either a low-dose (100-200mg per day for 12 weeks) or high-dose (250-400mg per day for 16 weeks) of Relacorilant. Outcome measures included the proportion of patients with clinically significant improvement in hypertension (decrease of ³ 5% in either mean 24-hour SBP or DBP from baseline) and hyperglycemia (decrease in HBA1c of ³ 0.5% from baseline or normalization or improvement ³50mg/dL of the 2-hr glucose value on OGTT, or decrease in antidiabetic medications). The study showed that 47.7% of the low-dose group and 63.6% of the high-dose group had clinically significant improvement in hypertension. Also, 15.4% of the low-dose group and 50% in the high-dose group met the criteria for clinically significant improvement in hyperglycemia. Furthermore, Relacorilant was seen to be associated with statistically significant increase in serum osteocalcin (mean change 3.00 μg/L, p < 0.01) indicating increased bone turnover and is correlated with a decrease in serum cortisol (22.0 (-127.0, 339.0) nmol/L (0.8 [-4.6, 12.3] μg/dL)(p = 0.239).²

In terms of safety, Relacorilant was generally better tolerated on the low-dose group compared to the high dose group. Adverse effects observed in the study were particularly back pain (31.4%), headache (25.7%), peripheral edema (25.7%), pain at the extremities (22.9%), nausea (22.9%) and diarrhea (20%%). A study by Donegan, et al., showed that  Relacorilant had  no apparent QTc prolongation even in supratherapeutic doses. ³ It was also not associated drug-induced vaginal bleeding as compared  with Mifepristone, as the former lacks activity at the progesterone-receptor.⁴

As of March 3, 2025, Relacorilant has been submitted to the United States Food and Drug Administration (U.S. FDA) for New Drug Application (NDA) for endogenous hypercortisolism but still pending approval. Indeed, further studies are still needed to better establish the role of this new agent. However, these initial findings provide a ray of hope for our patients with endogenous Cushing’s to have a better quality of life.⁵

References:

1. Fleseriu, M, Auchus, R., Bancos, I., et al. Consensus on diagnosis and management of Cushing disease: a guideline update. L D Endocrinol 2021; 9 (12) 847-875. DOI: 10.1016/S2213-8587(21)00235-7
2. Pivonello, R., Bancos, I., Feelders, R., Kargi, A., Kerr, J., Gordon, M., Mariash, C., Terzolo, M., Ellison, N., and Moraitis, A. Relacorilant, a selective glucocorticoid receptor modulator, induces, clinical improvements in patients with Cushing syndrome: results from a prospective, open-label phase F. Endocrinol. 2021; 12. DOI: 10.3389/fendo.2021.662865
3. Donegan, D., Pivonello, R., Stigliano, A., Lardo, P., Kearney, T., Mezosi, E., Ghigo, E., Giordano, R., Mariash, C., Feelders, R., Donaldson, K., Darpo, B., Xue, H., Custodio, J., Hand, A., and Moraitis, A. Recorilant, a selective glucocorticoid receptor modulator, in development for the treatment of patients with Cushing syndrome, does not cause prolongation of the cardiac QT interval. Endo P. 2024; 30 (2024) 11-18. DOI: 10.1016/j.eprac.2023.09.011
4. Melmed, S., Anchus, R., Goldfine, A., Rosen, C., Kopp, P. (2025). Williams Textbook of Endocrinology (15^th).
5. Sharma, S., Nieman, L., and Feelders,R. Cushing’s syndrome: epidemiology and developments in disease management. J Clin Epidem. 2015; 281-293. DOI: 10.2147/CLEP.S44336