Therapeutics: osilodrostat for Cushing’s disease

Published: 15-Jun-2020

Cushing’s disease is a rare condition in which the adrenal glands overproduce the hormone cortisol

It is caused by a pituitary tumour that leads to the release of too much adrenocorticotropin, the hormone that causes the adrenal glands to make cortisol. Patients with the disease may develop problems such as type 2 diabetes, high blood pressure, embolisms in the lungs and legs, fractures and a weakened immune system.

Novartis has developed a treatment: osilodrostat.1 This works by blocking the enzyme 11-beta-hydroxylase, which catalysis the final step of cortisol synthesis. It is designed for patients who cannot undergo pituitary surgery, which is the usual treatment, or for those who have had this surgery yet still have the symptoms of the disease.

In a proof-of-concept study, 12 patients were given 4 mg/day of osilidrostat in two equal doses, with the dose escalated every 14 days to 10, 20, 40 and 100 mg/d until urinary free cortisol (UFC) levels normalised.2

At that point, the dose was maintained until the study’s 70th day. All patients achieved normal UFC levels; 2 weeks after treatment stopped, the UFC had increased again. It was generally well tolerated, with the most common adverse events being fatigue, nausea and headache.

In an expansion, four of these patients plus 15 new ones were given the drug twice a day at the penultimate efficacious and tolerable dose in the previous trial for the follow-up group, and at 4 mg/day for the new patients and escalated every 2 weeks to 10, 20, 40 and 60 mg/day.3 The overall response rate was 89.5% at 10 weeks and 78.9% at 22 weeks.

A Phase III study has also been done in 137 adult patients with Cushing’s disease. In the initial 24-week, single arm, open label part, patients were given a starting dose of 2 mg twice a day, which could be increased to up to 30 mg twice a day.

After 24 weeks, cortisol levels had normalised in about half the patients, and 71 patients who needed no further dose increases were given the drug or placebo for a further 8-week double-blind withdrawal study.

At the end, 86% of those still getting the drug had normal cortisol levels, compared with 30% of the placebo group. The most common adverse events were adrenal insufficiency, headache, nausea, vomiting, fatigue and oedema.


  • S.G. Creemers, et al., J. Clin. Endocrinol. Metab. 104, 3437 (2019).
  • X. Bertagna, et al., J. Clin. Endocrinol. Metab. 99, 1375 (2014).
  • M. Fleseriu, et al., Pituitary 19, 138 (2016).

You may also like