First Approval for Osilodrostat for Cushing Syndrome, in EU

Miriam E. Tucker


November 15, 2019

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has given a positive opinion for osilodrostat for the treatment of Cushing syndrome in adults. This is effectively the first worldwide marketing authorization for the agent.

Cushing syndrome is a rare disorder of chronic hypercortisolism with significant burden, increased mortality, and decreased quality of life. Pituitary surgery is the recommended first-line treatment for most patients, but not all cases remit with surgery, and some patients require additional treatment.

Pasireotide (Signifor, Novartis), an orphan drug approved in the United States and Europe for the treatment of Cushing syndrome in patients for whom surgery fails or who are ineligible for surgical therapy, is only effective in a minority of patients.

Osilodrostat is an oral cortisol synthesis inhibitor that specifically works to control or normalize elevated cortisol levels by inhibiting 11β-hydroxylase, an enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland.

Its mechanism of action is similar to that of metyrapone, an older Cushing's drug, but osilodrostat has a longer plasma half-life and is more potent against 11β-hydroxylase.

Final approval by the European Commission is normally a formality granted within 60 days; osilodrostat will be available in Europe as 1-mg, 5-mg, and 10-mg film-coated tablets and will be made available under the brand name Isturisa.

It was developed by Novartis, but Recordati has acquired the worldwide rights to the agent.

Osilodrostat Should Be Initiated by Endocrinologist

Frequent side effects with osilodrostat include gastrointestinal disorders, fatigue, headache, and edema. The most common adverse event is adrenal insufficiency.

Because of that, the CHMP advises that the drug "be initiated and supervised by physicians experienced in endocrinology or internal medicine and with access to the appropriate facilities for monitoring of biochemical responses."

Phase 3 data from a multicenter, double-blind randomized study (LINC-3) of osilodrostat in 137 patients with Cushing syndrome were presented in March 2019 at the annual meeting of the Endocrine Society by Beverly M. K. Biller, MD, of the Neuroendocrine and Pituitary Tumor Center at Massachusetts General Hospital, Boston, as reported by Medscape Medical News.

Significantly more patients who were randomly assigned to receive osilodrostat maintained a mean urinary free cortisol (mUFC) response vs placebo at 34 weeks following a 24-week open-label period plus an 8-week randomized phase. Most patients experienced a rapid and sustained reduction in mUFC.

Patients also experienced improvements in clinical signs of hypercortisolism and in quality of life. The drug was generally well tolerated, and there were no unexpected side effects.

Commenting at that meeting, Julia Kharlip, MD, called the LINC-3 data "incredibly exciting because over 80% of people were controlled fairly rapidly" and said that "people could get symptom relief but also a reliable response. You don't have to wonder when you're treating a severely affected patient if it's going to work. It's likely going to work."

However, Kharlip, associate medical director of the Pituitary Center at the University of Pennsylvania, Philadelphia, cautioned that it remains to be seen whether osilodrostat continues to work in the long term, given that the older drug, metyrapone — which must be given four times a day, vs twice daily for osilodrostat — is known to become ineffective over time because the pituitary tumor eventually overrides the enzyme blockade.

A confirmatory 48-week phase 3 study, LINC-4, is expected to be completed in December 2019.

Detailed recommendations for the use of osilodrostat will be given in the summary of product characteristics, which will be published in the European public assessment report and made available in all official European Union languages after the marketing authorization has been officially granted by the European Commission.

At the time of the Endocrine Society meeting presentation, Biller was a consultant for and had received grants from Novartis and Strongbridge. Kharlip reported no relevant financial relationships.

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