Isturisa Leads to Rapid, Sustained Reduction in Cortisol Levels, Data Show

Treatment with Isturisa (osilodrostat) led to a rapid and sustained reduction in cortisol levels and was well-tolerated in people with Cushing’s disease, according to newly published data from the LINC-3 clinical trial.

The results were published in The Lancet Diabetes & Endocrinology, in the article “Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a doubleblind, randomised withdrawal phase.”

“The exciting data, published today, underscore the efficacy and safety of Isturisa in a prospective setting, and represent a significant advance for the management of patients with Cushing’s disease, a serious and potentially life-threatening rare condition,” Rosario Pivonello, MD, study co-author and professor at the Federico II University of Naples, said in a press release issued by Recordati Rare Diseases, which markets Isturisa.

Cushing’s disease is characterized by the excess production of the hormone cortisol. Isturisa is an oral medication that inhibits an enzyme, 11-beta-hydroxylase, that is involved in the production of cortisol, thereby reducing cortisol levels (and, consequently, Cushing’s symptoms).

Isturisa was approved by the U.S. Food and Drug Administration earlier this year for the treatment of Cushing’s disease, and also by the European Commission to treat endogenous Cushing’s syndrome. The medication recently became available to patients in the U.S., France, and Germany.

“Following the recent approval of Isturisa in the US and EU, we are excited to bring Isturisa to all of those patients who need it,” said Andrea Recordati, CEO of Recordati.

These approvals were largely based on the results of the Phase 3 clinical trial LINC-3 (NCT02180217). Trial data have previously been reported, and now have been published — meaning they have undergone peer review, a process in which experts who weren’t involved in the study evaluate the trial design and findings, to ensure proper scientific rigor.

LINC-3 was sponsored by Novartis, which developed Isturisa before the medication was acquired by Recordati.

The LINC-3 trial enrolled 137 people with Cushing’s disease (77% female, median age 40 years). Participants first received Isturisa for 26 weeks, with efficacy-based dose adjustments during the first 12 weeks. Then, participants with a complete response — those who had urinary-free cortisol levels below the upper limit of the normal range — at week 26 who also did not require a dose increase after week 12 (71 patients) were then randomly assigned to either continue with Isturisa (36 participants) or move to a placebo (35 participants) for eight more weeks.

Significantly more participants who continued on Isturisa maintained normal urine cortisol levels, compared to those who switched to the placebo (86% vs. 29%).

After the randomization period, all participants were treated with Isturisa up to week 48. At that point, 66% of participants had normal urine cortisol levels. Over the course of the study, 96% participants had normal urine cortisol levels at some point in time.

Broadly, reductions in urine cortisol levels were associated with improvements in clinical factors that are important for heart health, such as weight, body mass index, blood sugar, blood pressure, and total cholesterol.

The treatment was generally well-tolerated, with the most common adverse effects being nausea (42%), headache (34%), fatigue (28%), and adrenal insufficiency (28%). One patient’s death after the core study phase was deemed unrelated to the treatment.

“The publication of these data in Lancet Diabetes & Endocrinology confirms Isturisa as an effective new treatment option for patients with Cushing’s syndrome,” Recordati said.

Pivonello added: “I would like to thank all the patients who participated in the LINC-3 study, and their families, who have helped to bring this new and welcome treatment option to this underserved patient population.”

Another Phase 3 trial, LINC-4 (NCT02697734), is ongoing to confirm these results.

Additionally, a Phase 2 trial (NCT03708900) testing Isturisa in children with Cushing’s disease is currently recruiting at multiple locations in Europe. Additional information is available here.