Isturisa Rapidly Lowers Urine Cortisol Levels, Eases Disease-related Risks

Isturisa (osilodrostat), an approved oral therapy for Cushing’s disease, can rapidly normalize — in a median of 35 days — the levels of urine free cortisol in people with the disease, according to newly released data from the Phase 3 LINC-4 trial.

Treatment also led to sustained improvements in key measures linked to metabolism and heart function, including better control of blood sugar levels and blood pressure.

These findings, mostly concerning secondary trial goals, add to previous data showing that significantly more patients on Isturisa attained normal urine cortisol levels within three months of treatment than did those on placebo, the trial’s main goal.

“We are delighted that the positive and statistically significant data from the LINC-4 study have been presented at the Endocrine Society’s annual meeting. These data add to the robust body of evidence supporting Isturisa as an effective and well-tolerated treatment for patients with Cushing’s disease,” Andrea Recordati, CEO of Recordati, which markets the therapy, said in a press release. (The company acquired global rights to Isturisa from Novartis, its initial developer, in 2019.)

“Recordati is committed to improving the lives of patients with this serious yet underserved condition. On behalf of Recordati, I would like to thank all the patients, their families and carers, the investigators and the study collaborators who have contributed to LINC-4 and the Isturisa clinical program,” he added.

Mônica Gadelha, MD, PhD, a professor of endocrinology at the Universidade Federal do Rio de Janeiro in Brazil and a past advisory board member for Novartis, discussed these results at the 2021 ENDO meeting in the presentation, “Osilodrostat Is an Effective and Well-Tolerated Treatment for Cushing’s Disease (CD): Results From a Phase III Study With an Upfront, Randomized, Double-Blind, Placebo-Controlled Phase (LINC 4).”

Isturisa works by inhibiting an enzyme that plays a key role in cortisol production. Through this mechanism, it is expected to help lower, or even normalize, the hormone’s levels in the body to ease Cushing’s symptoms.

The LINC-4 study (NCT02697734) was designed to confirm the safety and efficacy of Isturisa in adults with Cushing’s, and was the first Phase 3 trial in this disease to start with a randomized, double-blind, placebo-controlled part, according to Recordati.

The trial followed the positive results of a prior Phase 3 study, called LINC-3 (NCT02180217), which found Isturisa to be superior to a placebo at keeping urinary cortisol levels within a normal range in adult Cushing’s patients.

In LINC-4, 73 patients were initially assigned to either Isturisa (48 people) or a placebo (25 people) for 12 weeks. After that, those in both groups were treated with Isturisa until week 48, and then given the option to continue treatment for up to 100 weeks.

As previously reported, the trial met its main goal, with 77% of patients on Isturisa showing a complete response — defined as having urinary free cortisol levels within a normal range — by the end of the 12-week randomization period, compared with 8% of those on a placebo.

The normalization of urine cortisol levels brought on by Isturisa also occurred rapidly, with treated patients seeing their hormone levels return to normal in a median of about one month (35 days).

A key secondary trial goal was also achieved, with 81% of patients in the overall population having a complete sustained response after 36 weeks.

Rapid and sustained normalization of urine cortisol levels was also accompanied by better control of blood pressure and blood sugar levels, evident after both 12 and 48 weeks of treatment.

Isturisa was well tolerated. The most common adverse events were joint pain (45%), decreased appetite (45%), fatigue (38%), nausea (37%) and headache (33%).

“I feel privileged to present these additional important findings at the Endocrine Society’s annual meeting, which represent a meaningful step forward in the optimal management of patients experiencing this life-threatening, devastating disease,” Gadelha said.

“Importantly, treatment with Isturisa was effective in normalizing mUFC [mean urinary free cortisol] levels in the majority of patients from the start of treatment, improved clinical signs of hypercortisolism and cardiovascular-related risk factors, and was well tolerated,” she added.