Japan OKs Isturisa for Endogenous Cushing’s

The Japanese Ministry of Health, Labour and Welfare (MHLW) has approved Isturisa (osilodrostat) to treat people with endogenous Cushing’s syndrome for whom pituitary brain surgery has not been effective or is not an option.

Recordati, the therapy’s developer, expects Isturisa to become available to patients in the country later this year.

“The MHLW’s approval of Isturisa as an effective and generally well-tolerated oral treatment option for patients with Cushing’s syndrome constitutes another major milestone for our Endocrinology franchise. We are committed to bringing Isturisa to all patients who need it,” Andrea Recordati, CEO of Recordati, said in a press release.

“On behalf of Recordati, I extend my 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 in bringing this therapy to patients in need,” he added. 

Isturisa is an oral medication that blocks an enzyme involved in the production of cortisol, a hormone whose levels are excessively high in people with Cushing’s syndrome, typically due to tumors in the brain’s pituitary gland (Cushing’s disease). These tumors lead to the excess release of adrenocorticotropic hormone, which in turn, stimulates cortisol production. 

Surgical removal of the pituitary tumor is the first-choice treatment for Cushing’s, but not all patients respond; in some the disease is recurrent, while others may not be able to undergo surgery. Reducing cortisol levels usually helps alleviating symptoms in these cases. 

Isturisa was approved by the U.S. Food and Drug Administration in 2020 to treat adults with Cushing’s disease for whom pituitary brain surgery was either not effective or not an option. In the European Union, Isturisa also was  approved in 2020 for the treatment of people with endogenous Cushing’s syndrome. 

All approvals, including the most recent in Japan, were based mainly on data from the Phase 3 LINC-3 clinical trial (NCT02180217), showing that Isturisa normalized cortisol levels in most adults with Cushing’s disease, while easing other clinical disease features. 

LINC-3 enrolled 137 patients who first completed a 26-week treatment regimen with Isturisa.

Participants whose urine cortisol levels dropped below the upper limit of the normal range after 26 weeks of treatment were assigned randomly to either continue taking Isturisa or move to a placebo for eight more weeks.

A much larger proportion of patients who continued on Isturisa maintained normal mean urinary free cortisol (mUFC) compared to those on a placebo (86% vs. 29%). 

Similar findings were seen in a small group of Japanese patients who participated in a Phase 2 trial (NCT02468193). Data from this study showed that Isturisa normalized cortisol levels in patients with endogenous Cushing’s syndrome whose disease was not caused by a pituitary tumor. 

“Isturisa is an important and appreciated therapy in treating patients with endogenous Cushing’s syndrome, including Cushing’s disease, a severe, potentially life-threatening rare disease,” said Akira Shimatsu, MD, from the National Hospital Organization Kyoto Medical Center.

“Until now, patients in need of medications to reduce cortisol levels have had few approved options, either with limited efficacy or with too many adverse effects. We now have a well-documented, effective oral treatment that represents a new therapeutic option that will help address the medical needs of this underserved patient population,” Shimatsu said. 

LINC-3 data also showed Isturisa was generally safe and well-tolerated. Adverse side effects associated with Isturisa occurred in at least 10% of patients; they included abnormal hormone levels, nausea, fatigue, physical weakness, headache, joint pain, decreased appetite, and vomiting.

“We are excited by the prospect of making Isturisa — an effective and well-tolerated medical treatment option — available to patients with Cushing’s syndrome in Japan and are planning to launch the product in the second half of this year,” said Satoshi Fujiwara, general manager of Recordati Rare Diseases Japan.

The ongoing Phase 3 LINC-4 trial (NCT02697734) aims to confirm these results. A Phase 2 trial (NCT03708900) assessing the safety and efficacy of Isturisa in children with Cushing’s disease also is ongoing. Recruitment is underway at multiple locations in Europe. More information is available here.