The US Food and Drug Administration approved osilodrostat (Isturisa) oral tablets for adults with Cushing disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease.

Cushing disease is a rare disease in which the adrenal glands make too much of the cortisol hormone. Osilodrostat is the first FDA-approved drug to directly address this cortisol overproduction by blocking the enzyme known as 11-beta-hydroxylase and preventing cortisol synthesis.

“The FDA supports the development of safe and effective treatments for rare diseases, and this new therapy can help people with Cushing disease, a rare condition where excessive cortisol production puts them at risk for other medical issues,” said Mary Thanh Hai, MD, acting director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research. “By helping patients achieve normal cortisol levels, this medication is an important treatment option for adults with Cushing disease.”

Cushing disease is caused by a pituitary tumor that releases too much of a hormone called adrenocorticotropin, which stimulates the adrenal gland to produce an excessive amount of cortisol. The disease is most common among adults between the ages of 30 to 50, and it affects women three times more often than men.

Cushing disease can cause significant health issues, such as high blood pressure, obesity, type 2 diabetes, blood clots in the legs and lungs, bone loss and fractures, a weakened immune system and depression. Patients may have thin arms and legs, a round red full face, increased fat around the neck, easy bruising, striae (purple stretch marks) and weak muscles.

Osilodrostat's safety and effectiveness for treating Cushing disease among adults was evaluated in a study of 137 adult patients (about three-quarters women) with a mean age of 41 years. The majority of patients either had undergone pituitary surgery that did not cure Cushing disease or were not surgical candidates. In the 24-week, single-arm, open-label period, all patients received a starting dose of 2 mg of osilodrostat twice a day that could be increased every 2 weeks up to 30 mg twice a day.

At the end of this 24-week period, about half of patients had cortisol levels within normal limits. After this point, 71 patients who did not need further dose increases and tolerated the drug for the last 12 weeks entered an 8-week, double-blind, randomized withdrawal study where they either received osilodrostat or a placebo (inactive treatment). At the end of this withdrawal period, 86% of patients receiving osilodrostat maintained cortisol levels within normal limits compared to 30% of patients taking the placebo.

The most common side effects reported in the clinical trial for osilodrostat were adrenal insufficiency, headache, vomiting, nausea, fatigue and edema (swelling caused by fluid retention). Hypocortisolism (low cortisol levels), QTc prolongation (a heart rhythm condition) and elevations in adrenal hormone precursors (inactive substance converted into a hormone) and androgens (hormone that regulates male characteristics) may also occur in people taking osilodrostat.

Osilodrostat is taken by mouth twice a day, in the morning and evening as directed by a health care provider. After treatment has started, a provider may re-evaluate dosage, depending upon the patient’s response.

Osilodrostat received Orphan Drug Designation, which is a special status granted to a drug intended to treat a rare disease or condition.

The FDA granted the approval of osilodrostat to Novartis.