Osilodrostat for Cushing syndrome

Background:
Endogenous Cushing syndrome denotes a group of rare diseases resulting from the body’s over-excretion of cortisol. It can be characterised as adrenocorticotrophic hormone (ACTH)–dependent or independent. The most common form of ACTH-dependent Cushing syndrome is Cushing disease, where there is a pituitary tumour that secretes ACTH, leading to an overproduction of cortisol.¹

For most people with Cushing disease, tumour removal surgery is the first-line treatment, with or without irradiation. When surgery is not an option, or excess cortisol persists or recurs after surgery, drug treatment may be needed. Osilodrostat is a new drug approved for the treatment of adults with endogenous Cushing syndrome.

Mechanism of action:
Osilodrostat is a potent inhibitor of 11-beta-hydroxylase, an enzyme that catalyses cortisol biosynthesis in the adrenal gland.²

Clinical trials:
Osilodrostat was evaluated in a phase 3 trial with 137 participants who had persistent or recurrent Cushing disease (median age 40 years, majority female).³ Most participants had previous pituitary surgery (88%) and/or previous drug therapies for Cushing disease (74%), and 16% had previous pituitary irradiation. People receiving other drug therapies for Cushing disease were included in the study following a drug washout period. The trial consisted of a 24-week open-label treatment period to establish an individualised therapeutic dose of osilodrostat (completed by 118 participants), followed by an 8-week double-blind, placebo-controlled, randomised withdrawal period, where participants who had achieved and maintained a complete clinical response (n=72/118) either continued osilodrostat at the same dose or switched to placebo. Complete clinical response was defined as a mean 24-hour urinary free cortisol concentration not greater than the upper limit of normal.

Seventy participants completed the randomised withdrawal period. More patients who continued osilodrostat maintained a complete response without any dose increases during this period compared with those on placebo (86.1% versus 29.4%).^3,4

In an open-label extension study (60 participants with median 87.1 weeks of osilodrostat exposure), 66.7% maintained a complete response.⁵

Adverse effects:
Hypocortisolism-related adverse events (mostly reported as adrenal insufficiency or glucocorticoid deficiency) occurred in 70/138 (51%) of patients across the entire study. These were typically mild to moderate in severity and resolved through dose reduction or interruption; however, 36% of these patients required glucocorticoid treatment.³

The most common adverse effects reported in the osilodrostat continuation group during the randomised withdrawal period of the trial were nausea (11%), arthralgia (8%) and headache (8%). Inhibition of 11-beta-hydroxylase is associated with the accumulation of adrenal steroid precursors and increased testosterone; in female participants, hirsutism and acne were reported in 11% and 12%, respectively.³

A decrease in serum potassium concentration was observed in some patients, with 7 (5%) patients developing severe hypokalaemia. QT interval prolongation was reported in 5 (4%) patients.³

Dosage and administration:
The starting dose of osilodrostat is 2 mg twice daily, gradually titrated (e.g. every 2 weeks) based on clinical response (aiming for normal cortisol concentrations) and tolerability. In patients of Asian ancestry, a starting dose of 1 mg twice daily is recommended. The maximum dose is 30 mg twice daily.4 In the clinical trial, the mean dose was 5 mg twice daily.³

Dose adjustment is not required for patients with renal impairment or mild hepatic impairment. Patients with moderate or severe hepatic impairment require reduced starting doses.⁴

Practice points:
Hypocortisolism-related events can occur at any time during treatment, so regular monitoring of cortisol concentrations (e.g. 24-hour urinary free cortisol, serum or plasma cortisol) is essential. Additional monitoring is recommended during periods of increased cortisol demand, such as physical or psychological stress, or when changing concomitant medications.⁴ Patients should be advised to report signs and symptoms associated with hypocortisolism (e.g. nausea, vomiting, fatigue, abdominal pain, loss of appetite, dizziness). If hypocortisolism is suspected, cortisol concentrations should be measured, and dose reduction or interruption of osilodrostat considered. Glucocorticoid replacement may be required in the case of adrenal insufficiency.

Precautions:
As there is a risk of QT prolongation with osilodrostat, an electrocardiogram should be performed prior to initiating treatment, after initiation (within 1 week), and when clinically appropriate. Caution is advised when co-administering osilodrostat with drugs that can prolong the QT interval, or in patients with significant cardiovascular disease (e.g. congestive heart failure, recent myocardial infarction, unstable angina). A washout period should be considered when switching from other drugs known to affect the QT interval such as pasireotide or ketoconazole.⁴

In clinical studies, osilodrostat demonstrated mild to moderate inhibition of some cytochrome P450 (CYP) enzymes, such as CYP2D6, CYP3A4/5, CYP2C19 and CYP1A2. Caution should be taken when co-administering osilodrostat with substrate drugs that have a narrow therapeutic range.⁴

Use in pregnancy and breastfeeding:
Osilodrostat should not be used in pregnant people based on animal studies showing a risk of reproductive harm. It is classified as Therapeutic Goods Administration pregnancy category D. It is unknown whether osilodrostat is excreted in human milk.⁴

Place in therapy:
Osilodrostat offers a new therapeutic option for patients with endogenous Cushing syndrome who have been unsuccessful with surgery or unable to receive surgery.

This new drug comment was finalised on 6 March 2025.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

 

References

1. Gadelha M, Gatto F, Wildemberg LE, Fleseriu M. Cushing's syndrome. Lancet 2023;402:2237-52.
2. Therapeutic Goods Administration. Australian Public Assessment Report for Isturisa. Department of Health and Aged Care; 2022. [cited 2025 Jan 22]
3. Pivonello R, Fleseriu M, Newell-Price J, Bertagna X, Findling J, Shimatsu A, 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. Lancet Diabetes Endocrinol 2020;8:748-61.
4. Therapeutic Goods Administration. Australian Product Information – Isturisa osilodrostat (as phosphate) 1 mg film-coated tablet blister pack. 2024. [cited 2025 Jan 22]
5. Gadelha M, Snyder PJ, Witek P, Bex M, Belaya Z, Turcu AF, et al. Long-term efficacy and safety of osilodrostat in patients with Cushing's disease: results from the LINC 4 study extension. Front Endocrinol (Lausanne) 2023;14:1236465.

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

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