With the FDA approval of Novartis AG’s Isturisa (osilodrostat), an oral treatment for adults with Cushing’s disease, Recordati SpA, of Milan, is planning its U.S. market launch for the second or third quarter of this year.

Recordati, which acquired Isturisa’s worldwide rights from Novartis in October for $390 million, expects sales to peak at $100 million annually. The treatment is for adults with Cushing’s disease, a rare endocrine disease caused by a pituitary adenoma that leads to cortisol overproduction, which Isturisa is designed to control. It’s the first FDA-approved 11‐beta‐hyrdoxylase inhibitor that addresses cortisol overproduction and synthesis.

There are already two approved medications: Signifor (pasireotide, also from Recordati) and Korlym (mifepristone, Corcept Therapeutics Inc.), as well as a couple of off-label options. Most patients can have the adenomas, which stimulate the adrenal gland to make cortisol, surgically removed but the disease recurs in about 50% of them. That’s when drugs are often prescribed: Ketoconazole and Metopirone (metyrapone, Laboratoire HRA Pharma) are used off-label as steroidogenesis inhibitors; Signifor activates somatostatin receptors in the pituitary adenoma; and Korlym works as a glucocorticoid receptor (GR) antagonist, blocking the effects of cortisol.

More competition, however, is not far behind as Dublin’s Strongbridge Biopharma plc has Recorlev (levoketonconazole), a cortisol synthesis inhibitor in a phase III trial to treat endogenous Cushing's syndrome. The top-line data are expected in the second quarter of 2020.

On Oct. 23, Milan’s Recordati acquired worldwide rights to osilodrostat from Novartis, which received $390 million in the deal. Recordati owes undisclosed milestone payments for the approval and market access of osilodrostat as well as royalties on sales of the drug. The FDA decision confirmed the orphan status of Isturisa, providing seven years of market exclusivity, Recordati officials said.

Osilodrostat is a steroidogenesis inhibitor working much like Metopirone, but it appears to be a more potent inhibitor of 11-beta hydroxylase. In the phase III LINC-3 study that led to the FDA approval, 86% of patients achieved normal mean urinary free cortisol at week 34, compared to 29% for placebo (p<0.001). By week 48, 66% of patients had achieved normal mean urinary free cortisol. The most common side effects, as reported by more than 20% of patients in the clinical trial for Isturisa, were adrenal insufficiency, headache, vomiting, nausea, fatigue and edema. Three-quarters of the 137 adults in the study were women. The mean age of the study’s subjects was 41.

Another phase III trial, LINC-4, is underway. The multicenter, randomized, double-blind interventional trial has 73 participants who will receive osilodrostat or placebo. The primary outcome measure is achieving a complete response mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at week 12. The study is set to be completed in January.

Cushing’s is an endocrine disease caused by a pituitary adenoma, a gland enlargement leading to cortisol overproduction. It can cause high blood pressure, obesity, type 2 diabetes, leg and lung blood clots, bone loss, bone fractures, hypercoagulability, a weakened immune system and depression.

Once properly diagnosed by an endocrinologist, about 70% of patients can have surgery to remove the benign adenomas stimulating the adrenal gland to make cortisol. But because the tumors are small, they often aren't fully removed, and about 50% of patients have recurrence of the disease. The disease most commonly affects adults ages 30 to 50, and three times more women than men.

Isturisa, for Cushing’s patients for whom pituitary surgery is not an option or has not been curative, was granted marketing authorization by the European Commission in January. It was designated an orphan medicine by the EMA in 2014.

Amid a global market sell-off, Recordati’s stock (REC.MI) sagged 4.5% on March 9. Recordati Rare Diseases Inc. is part of the rare diseases business within the Recordati Group, which launched a U.S. endocrinology business unit.