HRA Pharma Rare Diseases: First prospective study extension confirms that metyrapone is effective and safe for treating endogenous Cushing’s Syndrome in the long term

PROMPT is the first ever prospective study to test the long term efficacy and safety of metyrapone in patients with Cushing’s Syndrome in a real-life setting.

Evelina Paberze, COO of HRA Pharma Rare Diseases, says, “At HRA Pharma Rare Diseases, we are committed to the Cushing’s Syndrome community. Investing in PROMPT and demonstrating the effectiveness of metyrapone in treating endogenous Cushing’s Syndrome in the long term is part of our engagement.”

HRA Pharma Rare Diseases will present data from the six-month extension of PROMPT, the first ever prospective study designed to evaluate metyrapone long term efficacy and a good tolerability profile in patients with endogenous Cushing’s Syndrome. After confirming good efficacy and safety of metyrapone in the first phase of the study that ran for 12 weeks, the results of the six-month extension showed that metyrapone successfully maintains low Urinary Free Cortisol (UFC) levels with good tolerability. The data will be presented at the European Congress of Endocrinology 2021 on the 24th of May. 

Cushing’s Syndrome is a severe rare disease caused by an excess of cortisol in the body. It leads to increased mortality and significant morbidity, necessitating effective biochemical control. Endogenous Cushing's Syndrome is caused by pituitary, adrenal or ectopic tumors (adenomas or carcinomas) and is managed by controlling high cortisol levels in patients. 

Metyrapone is approved in Europe for the treatment of endogenous Cushing’s Syndrome based on observational retrospective studies published over more than 50 years. It works by inhibiting the 11-beta-hydroxylase enzyme, the final step in cortisol synthesis. 

PROMPT, a single arm, open-label, phase III/IV study involved the treatment of 50 patients with metyrapone over a 12-week (Wk12) titration period, assessing control by the mean of three UFC (mUFC) measurements. Patients whose mUFC was normal or did not exceed two-fold the upper limit of normal (ULN) at week 12 could enter the six-month extension period. A total of 41 patients were enrolled in the extension phase with 35 patients completing the extension; six patients dropped out due to adverse events or to a physician/patient decision not to continue. 

At the end of the extension study, 49% of patients had normal mUFC and another 23% had a decrease of mUFC ≥ 50% from baseline, while 31% had less than two times the ULN. The rates of responders were similar at the end of the first period and the end of the extension period at week 36 (80%, 95%CI 67-89 vs 71%, 95%CI 55-84).

Other results include:

• 27% of patients normalised their late night salivary cortisol (LNSC) level at the end of the extension
• Clinical improvement of physical symptoms and comorbidities and a good tolerability profile were sustained over time
• Only five additional patients had at least one study drug related adverse event (AE) during the extension, compared to the first period (baseline to week 12). Overall, 31/50 (62%) at week 36 had at least one study drug AE
• No adrenal insufficiency was reported during the extension period
• Clinically significant improvement in patients’ quality of life was observed with a mean increase of 10.4

Dr. Lynnette Nieman, chief of the Endocrinology Consultation Service at the U.S. National Institutes of Health, and the international coordinator of PROMPT, says, “The PROMPT study confirms that metyrapone is effective and safe for treating endogenous Cushing’s Syndrome in the long term. These extension results are significant given the unmet medical need for patients with this rare disease.”