Phase 3 Trial of Endogenous Cushing's Syndrome Treatment Meets Primary Endpoint

A pivotal phase 3 SONICS study evaluating Strongbridge Biopharma plc’s levoketoconazole (RECORLEV) for the treatment of endogenous Cushing’s syndrome achieved statistical significance of its pre-specified primary endpoint with 30% of patients achieving normalization of mean urinary free cortisol (UFC) at 6 months.

Key secondary endpoints were also met in the study, showing statistically significant and clinically meaningful improvements from baseline in cardiovascular risk markers.

“The robust effect of levoketoconazole in normalizing or decreasing UFC levels was complemented by key secondary endpoint data showing significant improvements in multiple markers for cardiovascular risk,” said Maria Fleseriu, MD, FACE, professor of Neurological Surgery and Medicine, and director of the Oregon Health Sciences University Northwest Pituitary Center, in a recent statement.

The open-label, single-arm SONICS phase 3 study enrolled 94 patients at centers in North America, Europe, and the Middle East, and it was comprised of 3 treatment phases. The first phase was a dose titration phase in which patients started levoketoconazole at 150 mg twice-daily (300 mg total daily dose), titrated in 150 mg increments with the goal of achieving a therapeutic dose—a dose resulting in UFC normalization—at which point titration was terminated. The second phase was a maintenance phase in which the dose was fixed and should not have been changed other than for safety reasons or loss of efficacy. At the end of the 6-month maintenance phase, the UFC response rate was measured. The third phase was an extended evaluation phase in which patients continue for another 6 months.

In order to be considered a UFC responder for the primary efficacy analysis, a patient must have met either 3 or 4 of the following criteria, according to the recent news release:

1. have completed the 6-month maintenance phase
2. have normal (at or below the ULN) mean 24-hour UFC on the basis of at least 2 (and up to 4) adequate 24-hour urine samples
3. must not have increased the dose of levoketoconazole used during the entire maintenance phase
4. patients with a recent history of pituitary radiation must have exhibited a rebound increase in mean UFC above the ULN following a 2-week minimum withdrawal of levoketoconazole at the end of maintenance phase

With 30% of patients achieving normalization of mean UFC following 6 months of maintenance treatment with levoketoconazol—without a dose increase (p<.025)&mdash;the study achieved statistical significance of its pre-specified primary endpoint. Secondary and exploratory endpoints of UFC response as well as sensitivity analyses were supportive of the primary endpoint.

Levoketoconazole also exhibited statistically significant and clinically meaningful improvements from baseline (p<.0001 for each) in regard to the key secondary endpoints of cardiovascular risk, which included fasting blood glucose, hemoglobin A1C, total cholesterol, low density lipoprotein (LDL)-cholesterol, body weight, and body mass index (BMI).

Based upon data collected through the 6-month maintenance phase, levoketoconazole was found to be generally well tolerated. Due to adverse events (AEs), 12 patients (12.8%) discontinued treatment with levoketoconazole. None of the patients discontinued treatment due to nausea, but 1 patient discontinued treatment due to headache, both of which were the 2 most commonly reported AEs. Of the 14 patients (14.9%) who reported 1 or more serious adverse events (SAEs), 4 had SAEs deemed drug-related by investigators. One patient death was reported; however, it was considered to be related to colon cancer, not levoketoconazole treatment.

“The impressive top-line results of the SONICS study suggest that levoketoconazole, the 2S,4R enantiomer of ketoconazole, is an effective and well tolerated cortisol synthesis inhibitor in Cushing’s syndrome,” commented Fred Cohen, MD, chief medical officer of Strongbridge Biopharma. “Based on these compelling data, we look forward to discussing the potential for accelerated approval of levoketoconazole with the FDA and to continuing our discussions with regulators around the world.”