Isturisa Shown To Reduce Cortisol Levels, Ease Cushing’s Symptoms

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with Isturisa (osilodrostat) rapidly normalized cortisol levels, eased symptoms, and improved the quality of life for people with Cushing’s disease, according to data from the Phase 3 LINC-4 trial.

“Isturisa enables most patients with Cushing’s disease to gain rapid control of their cortisol levels, which in turn provides relief from a host of undesirable symptoms,” Alberto Pedroncelli said in a press release. Pedroncelli is clinical development and medical affairs lead of global endocrinology at Recordati, which markets Isturisa.

Full results from the trial were reported in the study, “Randomized trial of osilodrostat for the treatment of Cushing’s disease,” published in The Journal of Clinical Endocrinology & Metabolism.

In Cushing’s disease, a tumor in the brain’s pituitary gland causes the body to produce excessive amounts of the hormone cortisol. Isturisa, which blocks cortisol production, is approved in the U.S. to treat adults with Cushing’s disease for whom pituitary surgery was ineffective or not feasible. It’s also approved to treat endogenous Cushing’s syndrome in Europe and Japan.

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The Phase 3 LINC-4 trial (NCT02697734) enrolled 73 people with Cushing’s disease that had persisted or recurred even after surgery and/or radiation therapy at 40 centers in 14 countries. Participants ranged in age from 19 to 67 years, about 84% were female, and most were white (67.1%) and Asian (23.3%).

For the first 12 weeks of the study, participants were randomized to receive Isturisa (2 mg twice daily) or a placebo. For the next 36 weeks, all were treated with Isturisa.

After those 12 weeks, significantly more participants given Isturisa than a placebo had normal cortisol levels in their urine (77% vs. 8%), meeting the study’s main goal.

The treatment benefits remained evident throughout the next portion of the study where all were given Isturisa. At 48 weeks, the overall response rate was about 80%.

Similar response rates were seen in patients regardless of whether they had received radiation therapy on the pituitary tumor, though researchers said these findings should be interpreted cautiously due to the small number of patients with a history of prior radiation therapy.

The median time toward achieving normal urine cortisol levels was about a month (35 days), both in patients who started treatment with Isturisa and in those who switched from a placebo at week 12.

Decreased cortisol levels were also seen in the blood and saliva following Isturisa treatment.

Isturisa “rapidly lowered cortisol excretion to normal in most patients with Cushing’s disease and maintained normal levels throughout the core phase of the study,” said Peter Snyder, MD, a professor at the University of Pennsylvania and senior author of the study.

The medication was shown to help normalize blood pressure, blood sugar, and cholesterol levels, while also reducing body weight and waist circumference — all of which is in line with counteracting cortisol’s effects. Other signs and symptoms of Cushing’s, such as fat accumulation, muscle wasting, and facial redness were also eased with treatment.

“Importantly, this normalization [in cortisol levels] was accompanied by improvements in cardiovascular and metabolic parameters, which increase morbidity and mortality in Cushing’s disease,” Snyder said.

Treatment with Isturisa also led to marked improvements in two quality of life measures, the Cushing’s Disease Health-Related Quality of Life Questionnaire (CushingQoL) and the Beck Depression Inventory second edition (BDI-II).

“Cortisol reductions were maintained throughout 48 weeks of treatment and were accompanied by improvements in clinical signs of hypercortisolism [excessive cortisol levels] and quality of life,” the researchers wrote.

Isturisa was generally well-tolerated and no unexpected safety findings were reported. The most common side effects with treatment included decreased appetite, arthralgia (joint pain), fatigue, and nausea.

According to Pedroncelli, the findings confirm the positive results of a previous Phase 3 trial called LINC-3 (NCT02180217), which served as the basis for Isturisa’s approvals.

About one in four LINC-4 participants had side effects related to abnormally low cortisol levels [hypocortisolism], as did roughly half of the LINC-3 patients. The difference is likely because dose escalations were carried out more slowly in LINC-4, the researchers said.

To minimize the likelihood of hypocortisolism side effects, the researchers recommended that “dose increases [of Isturisa] should not occur more frequently than once every 1–2 weeks and should be guided by the results of cortisol assessments and by the individual clinical response.”

LINC-4 was funded by Novartis, which initially developed Isturisa. Recordati acquired the global rights for the therapy in 2019.