The U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for osilodrostat (Isturisa) to treat endogenous hypercortisolemia in adults with Cushing's syndrome who cannot undergo surgery or for whom surgery was not curative. Announced by Recordati on April 16, 2025, this approval significantly expands the drug's previous indication, which was limited to patients with Cushing's disease, a specific subtype of Cushing's syndrome.
The expanded approval was supported by Isturisa's extensive clinical development program, which included over 350 patients across multiple studies. This regulatory decision addresses an important unmet need for patients with various forms of Cushing's syndrome beyond the pituitary-driven Cushing's disease.
"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, Professor of Medicine and Neurological Surgery and Director of the Pituitary Center at Oregon Health & Science University, who served as a global primary investigator for the LINC studies.
Understanding Cushing's Syndrome and Hypercortisolemia
Hypercortisolemia, characterized by elevated cortisol levels, is the underlying cause of endogenous Cushing's syndrome. While Cushing's disease specifically results from pituitary overstimulation (ACTH) of the adrenal glands, Cushing's syndrome encompasses all causes of pathological cortisol excess.
If left untreated, endogenous hypercortisolemia in Cushing's syndrome can lead to severe complications, including:
- Diabetes
- Osteoporosis
- Cardiovascular issues
- Increased infection risk due to immune system suppression
- Weight gain
- High blood pressure
- Muscle weakness
- Psychological symptoms including depression and anxiety
Mechanism of Action and Clinical Evidence
Osilodrostat is a cortisol synthesis inhibitor that works by blocking 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 had undergone surgery that failed to resolve the condition.
The clinical evidence supporting this expanded indication comes from multiple studies, including the Phase 3 LINC 3 and LINC 4 trials:
In the LINC 3 study, 137 patients with persistent or recurrent Cushing's disease treated with twice-daily osilodrostat experienced rapid reductions in mean 24-hour urinary free cortisol (UFC) concentration. These reductions were sustained alongside improvements in clinical signs of hypercortisolism, with the treatment remaining generally well-tolerated.
The LINC 4 study demonstrated that osilodrostat rapidly normalized mean UFC excretion in most patients with Cushing's 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.
Implications for Patient Care
Scott Pescatore, Executive Vice President of Rare Diseases at Recordati, emphasized the significance of this approval: "We are pleased that with the label expansion for Isturisa 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. Cushing's syndrome can often have a devastating impact on the lives of patients and their families."
The FDA had previously granted Orphan Drug Designation to osilodrostat for the treatment of endogenous Cushing's syndrome, recognizing the critical need for effective therapies for this rare condition.
Safety Considerations
Healthcare providers should be aware of potential side effects associated with osilodrostat, including:
- Low cortisol levels (hypocortisolism/adrenal insufficiency)
- Heart rhythm problems, including QT prolongation
- Increases in other adrenal hormone levels
- Low potassium (hypokalemia)
- High blood pressure (hypertension)
- Edema
- Hirsutism
- Acne (in women)
The most common side effects reported include adrenal insufficiency, fatigue, nausea, headache, and edema.
Patients taking osilodrostat require careful monitoring, particularly during the initial treatment phase and following dose adjustments. Physicians should conduct baseline and follow-up electrocardiograms and monitor for signs of adrenal insufficiency, which may require dose modification or temporary discontinuation of treatment.
With this expanded indication, osilodrostat provides an important therapeutic option for a broader population of patients suffering from the debilitating effects of Cushing's syndrome, particularly those for whom surgical intervention is not feasible or has proven insufficient.
