FDA Approves Label Expansion for Osilodrostat for Cushing's Syndrome

The US Food and Drug Administration (FDA) approved the supplemental New Drug Application (sNDA) for osilodrostat (ISTURISA) for endogenous hypercortisolemia in adults with Cushing’s syndrome who cannot have surgery or for whom it was not curative.1

Announced by Recordati on April 16, 2025, the regulatory approval expanded the previous approved indication for patients with Cushing’s disease, a subtype of Cushing’s syndrome. The company indicated the expansion was supported by positive results in the osilodrostat clinical development program.

“The expanded indication of osilodrostat is a significant advancement in the treatment of patients with Cushing’s syndrome for whom surgery is not an option or has not been curative, this therapy gives me the opportunity to normalize cortisol levels in these patients,” said Maria Fleseriu, MD, FACE, a professor of medicine and neurological surgery and director of the pituatary center at Oregon Health & Science University, and a global primary investigator for LINC studies.1

Hypercortisolemia is the underlying cause of endogenous Cushing's syndrome, marked by elevated cortisol levels. Cushing’s disease is elevated levels based on pituitary overstimulation of the adrenal glands, leading to various associated complications, including weight gain, high blood glucose, high blood pressure, and osteoporosis.2

Endogenous hypercortisolemia in Cushing’s syndrome, if left untreated, has been linked to severe diseases, including diabetes, osteoporosis, cardiovascular issues, and a higher risk of infection due to immune system suppression.

A cortisol synthesis inhibitor, osilodrostat prevents 11β-hydroxylase, an enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland. The FDA initially approved osilodrostat tablets in March 2020 for adults with Cushing’s disease who could not undergo pituitary gland surgery or have undergone the surgery but still have the disease.3

In the prospective, multicenter, open-label Phase 3 LINC 3 study, 137 patients with persistent or recurrent Cushing's disease treated with twice-daily osilodrostat experienced a rapid reduction in mean 24-hour urinary free cortisol (UFC) concentration. Remaining generally well-tolerated, osilodrostat sustained these reductions alongside improvements in clinical signs of hypercortisolism.4

Further results from the multicenter Phase 3 LINC 4 reported that osilodrostat rapidly normalized mean UFC excretion in most patients with Cushing disease and maintained this effect across an initial 12-week, randomized, double-blind, placebo-controlled period, followed by a 36-week, open-label treatment period.5

The regulatory agency later granted Orphan Drug Designation to osilodrostat for the treatment of endogenous Cushing's syndrome.1

“We are pleased that with the label expansion for [osilodrostat] in the U.S. to endogenous hypercortisolemia in patients with Cushing’s syndrome, this important unmet need can now be addressed with a further treatment modality,” said Scott Pescatore, executive vice president of rare diseases at Recordati. “Cushing’s syndrome can often have a devastating impact on the lives of patients and their families. Elevated cortisol levels in Cushing’s syndrome, if not properly controlled, can be associated with severe complications such as diabetes, osteoporosis, cardiovascular and increased risk of infections.”1

References

1. RECORDATI: FDA GRANTS ISTURISA® (OSILODROSTAT) EXPANDED INDICATION FOR THE TREATMENT OF ENDOGENOUS HYPERCORTISOLEMIA IN PATIENTS WITH CUSHING’S SYNDROME. RECORDATI. April 16, 2025. Accessed April 16, 2025. https://d2e3isjppdvvam.cloudfront.net/wp-content/uploads/2025/04/16063430/Press-Release_Isturisa-CS-approval.pdf.

2. Uwaifo GI, Hura DE. Hypercortisolism. [Updated 2023 Jul 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551526/

3. Commissioner of the FDA. FDA approves new treatment for adults with Cushing’s disease. U.S. Food and Drug Administration. March 6, 2020. Accessed April 16, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-adults-cushings-disease.

4. Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase [published correction appears in Lancet Diabetes Endocrinol. 2020 Sep;8(9):e4. doi: 10.1016/S2213-8587(20)30275-8.]. Lancet Diabetes Endocrinol. 2020;8(9):748-761. doi:10.1016/S2213-8587(20)30240-0

5. Gadelha M, Bex M, Feelders RA, et al. Randomized Trial of Osilodrostat for the Treatment of Cushing Disease. J Clin Endocrinol Metab. 2022;107(7):e2882-e2895. doi:10.1210/clinem/dgac178