TOPLINE:

A pooled analysis of data from three clinical trials found that osilodrostat rapidly lowered urinary free cortisol levels in patients with Cushing disease within 4-12 weeks and maintained control for up to 108 weeks. Doses ≤ 10 mg/d were sufficient to achieve biochemical control in most patients, and adverse events were mostly manageable, with the frequency declining during follow-up.

METHODOLOGY:

• LINC 2, LINC 3, and LINC 4 were clinical trials that showed that osilodrostat rapidly reduced 24-hour mean urinary free cortisol levels, produced sustained improvements in clinical signs and quality of life, and was generally well tolerated.
• A pooled analysis of the three trials looked at data from a total of 229 patients who had mean urinary free cortisol levels greater than 1.3 or 1.5 times the upper limit of normal; all study participants received treatment with osilodrostat starting at 2 mg twice daily, with a median average dose per patient of 6.8 mg/d for a mean duration of 113.7 weeks.
• Analyses focused on the proportion of patients who achieved control of mean urinary free cortisol levels, defined as not exceeding the upper limit of normal, along with the assessment of time to first control and sustainability of response.
• Safety was evaluated on the basis of the overall number of adverse events, adverse event rates by time interval, and management of such events.

TAKEAWAY:

• Approximately 80% of patients achieved their individual maximum osilodrostat dose during the first 12 weeks of treatment, with nearly 60% requiring dose down-titration thereafter; the median osilodrostat dose leading to first control of mean urinary free cortisol levels was 10 mg/d.
• Control of mean urinary free cortisol levels was achieved within 4-12 weeks and sustained until 108 weeks; the median time to first control was 35 days and increased with increasing baseline mean urinary free cortisol levels.
• Patients younger than 65 years and those without prior medical therapy for hypercortisolism achieved control more rapidly than older patients and those with prior medical therapy.
• The drug was generally well tolerated, but 16.2% of patients discontinued treatment because of adverse events. Hypocortisolism-related adverse events occurred more frequently during the first 12 weeks of treatment than in the long term.

IN PRACTICE:

“Lifelong monitoring for long-term maintenance of normal cortisol levels and to detect AEs [adverse events] early to ensure prompt intervention is advised,” the authors wrote.

SOURCE:

The study was led by Maria Fleseriu, Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health & Science University in Portland, Oregon. It was published online in The European Journal of Endocrinology.

LIMITATIONS:

Due to measurement intervals of 2-3 weeks during early study stages, the exact timing of achievement of mean urinary free cortisol control could not be precisely determined. Study design differences resulted in varying levels of osilodrostat exposure at different timepoints. Osilodrostat dose-titration decisions varied between studies. 

DISCLOSURES:

This study was funded by Novartis Pharma. Some authors disclosed receiving grants, consulting fees, honoraria, speaker fees, and payments from and having other ties with various pharmaceutical companies. Two authors declared being current or former employees of Recordati, the developer of osilodrostat.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.