Isturisa (also known as osilodrostat or LCI699) is an approved treatment originally developed by Novartis but now acquired by Recordati to treat people with Cushing’s disease, a condition caused by excessive levels of the hormone cortisol.

Because of the promise it showed in preclinical studies, the European Medicines Agency (EMA) granted Isturisa orphan drug status as a Cushing’s syndrome treatment in 2014. Isturisa was later granted approval by the European Commission (EC) as a treatment for endogenous Cushing’s syndrome.

Doctors make a distinction between Cushing’s syndrome and Cushing’s disease. When the adrenal gland produces excessive amounts of cortisol, the condition is called Cushing’s syndrome. When a pituitary gland tumor secretes excessive amounts of adrenocorticotropic hormone (ACTH), the disorder is referred to as Cushing’s disease.

How does Isturisa work?

Isturisa is an oral medicine that inhibits an enzyme called 11-beta-hydroxylase that is involved in cortisol production. Blocking the enzyme prevents excessive cortisol production, normalizing the levels of the hormone in the body and reducing the symptoms of Cushing’s disease.

Isturisa in clinical trials

A Phase 2 clinical trial (NCT01331239) investigated the safety and efficacy of Isturisa’s as a Cushing’s disease treatment. The trial that concluded in October 2019 was initially named LINC-1 but, through a study protocol amendment, patients who completed the study could continue into a second phase called LINC-2.

The company published findings that covered both patient groups in the journal Pituitary. They showed that Isturisa helped reduce cortisol levels in the urine. In the 22-week study, patients whose cortisol levels were more than three times the upper normal limit took an initial dose of either 4 mg per day or 10 mg per day of Isturisa. The dose was increased every two weeks to 60 mg per day until cortisol levels equaled or were below the upper normal limit. The main objective of the study was to normalize cortisol levels or cut them in half from the start of the treatment to the 10th and 22nd weeks. Isturisa reduced cortisol levels in all of the patients by week 22. Seventy-nine percent of patients achieved normal cortisol levels by then. Even though patients tolerated the treatment well, some of them experienced side effects. These included weakness, lack of energy, acne, and adrenal insufficiency, or the adrenal gland being unable to produce enough hormones.

A Phase 3 clinical trial (NCT02180217) called LINC-3 also assessed the safety and efficacy of Isturisa in 137 patients with Cushing’s disease. The trial included a 26-week period where all patients received Isturisa, followed by an eight-week period where they were randomized to continue Isturisa or take a placebo. Afterward, patients could choose to continue taking Isturisa for another 12-weeks.

The results of this trial showed that 86% of Isturisa-treated patients had normal urinary cortisol levels compared to 29% of placebo-receiving patients at the end of the 34-week period. These results were sufficient for the company to get approval to market Isturisa at three dosages (1, 5, and 10 mg oral tablets) for endogenous Cushing’s syndrome from the EC in January 2020.

A multi-center, randomized, double-blind, placebo-controlled Phase 3 trial (NCT02697734) called LINC-4 is also evaluating the safety and efficacy of Isturisa as a Cushing’s disease therapy. During the trial, patients will receive treatment or placebo through a 12-week period followed by 24-weeks of treatment. The mean urinary cortisol levels will be checked at 12, 36, and 48 weeks to see which patients have achieved normal cortisol levels. The study is still ongoing but no longer recruiting participants. It is expected to be completed in January 2021.

A roll-over Phase 2 study (NCT03606408) is currently recruiting patients worldwide, who have successfully completed any of the previous clinical trials. Patients can continue to take the dosage that they received during the initial trial. The aim of this study is to assess the long-term effects of Isturisa for up to five years.

A Phase 2 clinical trial (NCT03708900) is currently recruiting an estimated 12 pediatric patients (ages, 6 to 18) with Cushing’s disease. The study will investigate the pharmacokinetics (movement in the body), pharmacodynamics (effect on the body), and tolerability of the treatment. Participants will receive one of the three approved dosages for 12 weeks to 12 months. The trial is expected to conclude in November 2022.

 

Last updated: Jan. 19, 2020

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