Isturisa Approved in Europe for Treating Endogenous Cushing’s Syndrome

Recordati‘s inhibitor of cortisol synthesis, Isturisa (osilodrostat), has been approved by the European Commission (EC) for the treatment of people with endogenous Cushing’s syndrome, the company announced.

The decision follows a European Medicines Agency (EMA) committee recommendation in November to approve Isturisa for that purpose. The therapy will be available in three dosages: 1 milligram (mg), 5 mg, and 10 mg film-coated tablets.

“We are very pleased with the approval of Isturisa (osilodrostat) by the European Commission,” Andrea Recordati, CEO of Recordati, said in a press release. “Recordati Rare Diseases is committed to making this innovative treatment available for all patients suffering from endogenous Cushing’s syndrome worldwide and the European approval and subsequent launch is an important first step in this direction.”

Isturisa is an oral treatment that inhibits an enzyme called 11-beta-hydroxylase, which is involved in cortisol synthesis. Blocking the enzyme prevents excessive cortisol production, which normalizes the hormone’s levels in the body, reducing Cushing’s disease symptoms.

The therapy works in a similar manner as the commonly used treatment Metopirone (metyrapone), but with stronger inhibitory activity and better stability.

Isturisa was developed originally by Novartis, but was acquired by Recordati in July. It has been granted orphan drug status in Europe for people with Cushing’s syndrome, a designation that provides, among other incentives, market exclusivity for 10 years.

The approval was based on data from the LINC-3 Phase 3 clinical trial (NCT02180217), which showed that Isturisa was superior to a placebo at returning urinary cortisol levels to normal levels.

The trial included 137 people with persistent Cushing’s disease, who first received Isturisa for 26 weeks and were then assigned randomly to continue Isturisa or switch to a placebo for an additional eight weeks. Participants then could receive Isturisa in an open-label extension segment lasting another 12 weeks.

The trial’s main goal was to determine the proportion of patients with normal cortisol levels at 34 weeks, without requiring dose increases during the randomized part of the trial — an objective that was met. Results showed that significantly more patients taking Isturisa (86%) attained this goal, compared with 29% of those on placebo.

The most common side effects of Isturisa were nausea, headache, and fatigue. By the end of the 48-week study period, 18% of patients had discontinued treatment, 11% of which were due to adverse events.

A Phase 3 trial — LINC-4 (NCT02697734) — is ongoing to confirm these findings in 69 patients with Cushing’s disease. Their excess cortisol is caused by a tumor in the pituitary gland producing too much of the adrenocorticotropic hormone.

In this trial, patients randomly will receive Isturisa or a placebo in the first 12 weeks, after which all participants will be given Isturisa for another 36 weeks. The main goal is to determine the proportion of patients achieving normal cortisol levels at week 12. Secondary measures include similar responses at later time intervals.

In an upcoming Phase 2 trial (NCT03708900), researchers will assess the safety and effectiveness of Isturisa in children with the disease who are ineligible for surgical treatment, have had disease recurrence after surgery, or are awaiting surgery. Participants are still being recruited for that study.