Osilodrostat Approval Status for Non-ACTH Dependent Cushing's Syndrome
No, osilodrostat (Isturisa) is NOT approved for non-ACTH dependent Cushing's syndrome. The FDA label explicitly restricts its indication to adult patients with Cushing's disease (ACTH-dependent) for whom pituitary surgery is not an option or has not been curative 1.
FDA-Approved Indication
- Osilodrostat is approved only for Cushing's disease, which is specifically ACTH-dependent hypercortisolism caused by a pituitary corticotroph adenoma 1.
- The FDA label makes no mention of approval for ACTH-independent (adrenal) causes of Cushing's syndrome 1.
Regulatory Context
- The European Medicines Agency (EMA) approved osilodrostat in 2020 for "endogenous Cushing's syndrome in adults," which is a broader indication than the FDA approval 2.
- However, the FDA approval remains restricted to Cushing's disease specifically 1.
Off-Label Use in ACTH-Independent Disease
While not FDA-approved for this indication, emerging evidence suggests osilodrostat may be effective in ACTH-independent Cushing's syndrome:
- Clinical experience is accumulating for off-label use in ectopic and adrenal Cushing's syndrome, with reports showing efficacy in reducing cortisol levels across all etiologies 3.
- A 2025 review emphasizes that osilodrostat can achieve cortisol control in adrenal Cushing's syndrome when management is individualized according to disease severity 3.
- Real-world case reports demonstrate successful use in non-pituitary causes, though this represents off-label prescribing 3.
Mechanism and Rationale
- Osilodrostat inhibits 11β-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol synthesis in the adrenal cortex 4, 5.
- This mechanism of action is independent of ACTH levels, meaning it blocks cortisol production regardless of whether hypercortisolism is ACTH-dependent or ACTH-independent 5.
- The drug achieves high rates of cortisol normalization through direct adrenal steroidogenesis inhibition 4.
Clinical Guideline Recommendations
For ACTH-independent Cushing's syndrome, guidelines prioritize different approaches:
- Surgery (laparoscopic adrenalectomy for adrenal adenoma) remains first-line treatment for adrenal causes 4.
- When medical therapy is needed for adrenal Cushing's syndrome, guidelines from 2021 discuss adrenal steroidogenesis inhibitors broadly but do not specifically recommend osilodrostat for ACTH-independent disease 4.
- Ketoconazole and metyrapone are the traditional steroidogenesis inhibitors mentioned for various Cushing's syndrome etiologies 4.
Important Caveats
- Prescribing osilodrostat for ACTH-independent Cushing's syndrome constitutes off-label use in the United States, requiring informed consent and careful documentation 1.
- The phase III trial data supporting FDA approval came predominantly from Cushing's disease patients, not adrenal or ectopic cases 2, 6.
- Insurance coverage may be problematic for off-label indications despite mechanistic rationale for efficacy 3.
In summary: Osilodrostat is FDA-approved exclusively for Cushing's disease (ACTH-dependent), not for adrenal or other ACTH-independent causes, though off-label use in these conditions is being explored in clinical practice 1, 3.