Osilodrostat, formerly known as LCI699, is an oral treatment that inhibits an enzyme called 11-beta-hydroxylase, which is involved in cortisol production. Blocking the enzyme prevents excessive cortisol production, thereby normalizing the hormone’s levels in the body, and 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.
Osilodrostat, which was originally developed by Novartis but is now being developed by Recordati after it acquired the worldwide rights for marketing osilodrostat, will be available in three dosages: 1 milligram (mg), 5 mg, and 10 mg film-coated tablets.
In its recommendation, the EMA’s Committee for Medicinal Products for Human Use (CHMP) stated that the dosing should be initiated and supervised by physicians experienced in endocrinology or internal medicine, and that patients should be monitored.
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 findings were shared at the Endocrine Society Annual Meeting (ENDO 2019) in a talk, titled “Osilodrostat Treatment in Cushing’s Disease (CD): Results from a Phase III, Multicenter, Double-Blind, Randomized Withdrawal Study (LINC 3).”
Investigators in an ongoing Phase 3 trial — called LINC-4 (NCT02697734) — are currently confirming their findings in 69 patients with persistent or recurrent Cushing’s disease, whose 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.
An upcoming Phase 2 trial (NCT03708900) will test the safety and efficacy of osilodrostat in children with the disease who are ineligible for surgical treatment, have had disease recurrence after surgery, or are awaiting surgery.
So far, the most common side effects of osilodrostat treatment in adults are gastrointestinal disorders, edema (swelling), headache, and fatigue. The most serious common side effect is adrenal insufficiency.