RARE Daily

Recordati’s Experimental Cushing’s Disease Therapy Hits Endpoint in Phase 3 Study

June 17, 2020

Rare Daily Staff

Recordati Rare Diseases reported its experimental drug Isturisa achieved its primary endpoint in a phase 3 study of patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.

Cushing’s disease is a form of Cushing’s syndrome, in which chronically elevated cortisol levels are triggered by a pituitary adenoma secreting excess adrenocorticotropic hormone (ACTH). It is a rare, serious, and difficult-to-treat disease that affects approximately one to two patients per million per year. Prolonged exposure to elevated cortisol levels is associated with considerable morbidity, mortality and impaired quality of life as a result of complications and comorbidities.

Isturisa is a cortisol synthesis inhibitor that works by preventing 11-betahydroxylase, an enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland, from being created. In March 2020, the U.S. Food and Drug Administration granted marketing authorization for Isturisa in the United States. It is available as 1 mg, 5 mg, and 10 mg film-coated tablets.

LINC-4 is a large randomized, double-blinded, multicenter, 48-week trial with an initial 12-week placebo-controlled period to evaluate the safety and efficacy of Isturisa in patients with Cushing’s disease. The primary endpoint in the LINC-4 trial is the proportion of patients randomized to Isturisa and placebo, separately, with a mean urinary free cortisol (mUFC) level equal or lower than the upper limit of normal (ULN) at the end of the 12-week placebo-controlled period.

The key secondary endpoint is the proportion of patients in both arms combined with a mUFC ≤ULN after 36 weeks. LINC-4 involved 73 patients with persistent or recurrent Cushing’s disease or those with de novo disease who were not candidates for surgery.

Data from the LINC-4 study demonstrate that a significantly higher proportion of patients receiving Isturisa achieve normal mUFC, the primary treatment goal for Cushing’s disease, after 12 weeks of treatment versus placebo (77 percent vs 8 percent).

Improvements in (mUFC) levels were sustained over 36 weeks of treatment (81 percent of patients). Recordati said Isturisa is well tolerated and has a manageable safety profile, with the most common adverse events in LINC-4 being arthralgia, decreased appetite, fatigue, and nausea. The findings from LINC-4, the first phase 3 study of a medical therapy in Cushing’s disease to contain an upfront placebo-controlled phase, builds upon existing clinical evidence and affirms the effectiveness of Isturisa  in this hard-to-treat patient population.  

“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,” said Richard Feelders, professor of endocrinology at the Erasmus University Medical Center, Rotterdam. “Data from this important phase 3 study show that Isturisa is an effective and well-tolerated therapy for Cushing’s disease, which significantly reduces and normalizes mUFC levels in most patients.”

Photo: Richard Feelders, professor of endocrinology at the Erasmus University Medical Center, Rotterdam

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