The U.S. Food and Drug Administration (FDA) gave Italian firm Recordati and Novartis’ Isturisa (osilodrostat) the greenlight for adults with Cushing’s disease who either can’t have pituitary gland surgery or who have had the surgery but still have the disease. Cushing’s disease is a rare illness where the adrenal glands produce too much of the hormone cortisol. Recordati acquired the drug from Novartis in June 2019.
Isturisa is the first drug approved that blocks an enzyme called 11-beta-hydroxylase, preventing synthesis of cortisol. The disease is caused by a pituitary tumor that releases excess amounts of a hormone called adrenocorticotropin. This stimulates the adrenal gland to produce higher amounts of cortisol.
“We are pleased with the FDA’s recognition of Isturisa as an effective and safe treatment for patients with Cushing’s disease,” said Andrea Recordati, chief executive officer of Recordati. “We extend our deepest gratitude to the patients who participated in the clinical trials and their families and caregivers who supported them. We also appreciate the hard work of the investigators, clinicians and study staff to bring this therapy to patients in need. Recordati Rare Diseases is committed to working to ensure everyone who needs access to this therapy will receive it.”
Cushing’s disease affects women three times more than men and is most often diagnosed in adults between the ages of 30 and 50. It can result in 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 are often noted to have thin arms and legs, a round red full face, increased fat around the neck, bruise easily, have purple stretch marks and weak muscles.
“The FDA supports the development of safe and effective treatments for rare diseases, and this new therapy can help people with Cushing’s disease, a rare condition where excessive cortisol production puts them at risk for other medical issues,” said Mary Thanh Hai, 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’s disease.”
The approval was built on the Phase III LINC-3 clinical trial of 137 adults, about 75% of who were women, with a mean age of 41 years. The majority either had pituitary surgery that didn’t cure the disease or who were not candidates for the surgery. In the 24-week, single-arm, open-label period, all patients received a starting dose of 2 milligrams of Isturisa twice a day that could be increased every two weeks up to 30 mg twice a day. At the end of the 24-week period, approximately half of patients had normal cortisol levels. At that time, 71 patients who did not need dose increases and tolerated the drug for at least 12 weeks joined an eight-week, double-blind, randomized withdrawal trial where they were given either Isturisa or a placebo. At the end of this withdrawal period, 86% of patients receiving the drug maintained cortisol levels with normal limits compared to 30% of placebo patients.
Isturisa was granted Orphan Drug Designation. The most common side effects observed were adrenal insufficiency, headache, vomiting, nausea, fatigue and swelling caused by fluid retention. Some patients reported low cortisol levels, QTc prolongation, a heart rhythm condition, and increased levels of adrenal hormone precursor and androgens.
The drug was approved for Cushing’s disease in January by the European Commission.