Isturisa Shows Sustained Responses in Cushing’s Disease Patients in LINC-4 Trial

Isturisa (osilodrostat), an approved therapy for Cushing’s disease, continues to demonstrate high and sustained responses in patients for whom pituitary gland surgery is not an option or whose disease returned after surgery, findings from a Phase 3 trial show.

The LINC-4 study (NCT02697734) showed that significantly more patients on Isturisa attained normal cortisol levels in their urine within three months of treatment than did those on placebo, meeting its primary goal. Most patients retained normal urinary cortisol levels at nine months.

“Cushing’s disease is a chronic and debilitating condition that can be extremely challenging to manage and, if left inadequately treated, can have a significant impact on patients’ quality of life and increase the risk of mortality,” Richard Feelders, MD, a professor of endocrinology at Erasmus University Medical Center, in Rotterdam, said in a press release.

“Data from this important Phase III study show that Isturisa (osilodrostat) is an effective and well-tolerated therapy for Cushing’s disease, which significantly reduces and normalizes mUFC [mean urinary free cortisol] levels in most patients. These data are encouraging given the high unmet medical need for patients with this rare disorder,” Feelders added.

People with Cushing’s disease have excess cortisol in their blood due to a tumor in their pituitary gland that produces too much of the adrenocorticotropic hormone. This hormone acts on the adrenal glands that sit atop the kidneys, telling them to secrete cortisol.

Isturisa, originally developed by Novartis and acquired by Recordati last year, is an oral medicine that inhibits an enzyme that is essential for cortisol synthesis. This helps reduce or even normalize this hormone’s levels in the body, easing Cushing’s symptoms.

The therapy was recently approved in the U.S. for Cushing’s disease patients whose disease returned after pituitary gland surgery or who cannot undergo surgery. In the European Union, Isturisa is approved for a broader population: those with endogenous Cushing’s syndrome, which include anyone whose excess cortisol is caused by a tumor, be it in the pituitary gland or not.

The approvals were supported by data from the LINC-3 Phase 3 trial (NCT02180217), which showed that Isturisa was superior to a placebo at keeping urinary cortisol levels under normal levels in people with persistent Cushing’s disease.

This trial included 137 patients given Isturisa at doses ranging up to 30 mg twice-a-day for 26 weeks. Those with a complete response — deemed as having urinary free cortisol levels below the upper limit of the normal range — at week 26 who also did not required a dose increase after week 12 (71 patients) were then randomly assigned to either continue with Isturisa or move to placebo for eight more weeks.

LINC-3 met its primary goal, showing that significantly more patients who remained on Isturisa (86%) had normal urinary cortisol levels at week 34 without requiring dose increases, compared to 29% of those switched to a placebo.

LINC-4 was designed to confirm the safety and efficacy of Isturisa in 73 Cushing’s disease patients. But rather than randomizing patients to continuing with, or stopping, treatment after an initial period on Isturisa, people were randomized from the study’s start to either Isturisa or placebo.

In a first part lasting 12 weeks, patients received oral Isturisa in doses up to 30 mg, or a placebo. People in both groups were then given Isturisa until week 48, when they could choose to continue treatment for up to 100 weeks. According to Recordati, this was the first Phase 3 trial in Cushing’s disease with an upfront placebo-controlled part.

The trial’s primary goal is to determine the percentage of patients achieving a complete response, or normal mean urine free cortisol levels, at week 12. Secondary measures include the complete response rate by week 36, the percentage change in mean urinary free cortisol, and the time to first control of urine free cortisol. Health-related quality of life is also being assessed.

Results shared by Recordati showed that LINC-4 met its primary goal, with 77% of patients on Isturisa showing a complete response after the 12-week randomized period, compared to 8% of those on a placebo. These responses were sustained, with 81% of patients in the overall population having a complete response after 36 weeks.

Isturisa was also well tolerated, with a manageable safety profile. The most common adverse events were joint pain, decreased appetite, fatigue, and nausea.

“The compelling topline LINC-4 data confirm the effectiveness of Isturisa for the treatment of this rare, potentially life-threatening disease,” said Andrea Recordati, the company’s CEO.

“We are deeply grateful to the patients, investigators, clinicians and study staff whose ongoing participation in the clinical development of Isturisa has helped bring this therapy to patients in need,” Recordati concluded.