Cushing’s syndrome treatment maintains reductions in urinary free cortisol for 12 months
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Most adults with Cushing’s syndrome receiving levoketoconazole twice daily maintained reductions in mean urinary free cortisol levels during a 12-month maintenance period, according to findings from the SONICS study extended evaluation.
“The SONICS study demonstrated efficacy of levoketoconazole in normalizing mean urinary free cortisol during dose-titration and durability of response via a fixed-dose, 6-month maintenance phase and also provided evidence of improvement in biomarkers of Cushing’s syndrome comorbidities at the end of the maintenance phase,” Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health & Science University in Portland, and co-editor for Healio | Endocrine Today, and colleagues wrote in a study published in the European Journal of Endocrinology. “The prospective extended evaluation of the SONICS study described here included safety and efficacy evaluations through a median total exposure of approximately 15 months and further supports a role for levoketoconazole in long-term medical therapy for patients with endogenous Cushing’s syndrome.”
As Healio previously reported, the FDA approved levoketoconazole (Recorlev, Xeris Biopharma) in January after positive efficacy and safety results from the phase 3 SONICS and LOGICS studies that revealed the agent normalized mean urinary free cortisol concentrations without a dose increase for most adults. In the extended evaluation, 60 adults with a confirmed diagnosis of Cushing’s syndrome and 24-hour mean urinary free cortisol 1.5 times greater than the upper limit of normal who completed the SONICS study’s 6-month maintenance phase were enrolled for an additional 6 months of maintenance where levoketoconazole treatment continued without a change in dose. Assessments were completed at 9 and 12 months. Mean urinary free cortisol was measured through two to four 24-hour urine samples collected at each visit. Late-night salivary cortisol was measured through saliva samples collected between 11 p.m. and midnight on one or two nights. Blood samples were collected to measure free cortisol. Researchers also analyzed other biomarkers and clinical parameters of Cushing’s syndrome comorbidities, patient-reported quality of life and depression, and patient safety.
Improvements in mean urinary free cortisol maintained
Of the study cohort, 65% were receiving 600 mg or less of levoketoconazole daily at the start of the extension period, with a median average daily dose of 569 mg. Forty-six of the 60 participants completed the final visit at 12 months.
Mean urinary free cortisol was 528.1 nmol/24 hours at baseline. Compared with baseline, mean urinary free cortisol decreased to 147.4 nmol/24 hours at 6 months. The reduction in urinary free cortisol was sustained at 9 months with a mean level of 170.8 nmol/24 hours and at 12 months with a mean level of 180.6 nmol per 24 hours (P < .0001 for all). The proportion of participants with normalized mean urinary free cortisol was 61% at 6 months, 55% at 9 months and 41% at 12 months. The percentage of adults with either mean urinary free cortisol normalization or a 50% reduction in levels from baseline was 78% at 6 months, 82% at 9 months and 68% at 12 months.
A decrease in mean late-night salivary cortisol was observed only at 6 months for the study cohort (P = .028) and no changes in random serum cortisol were observed at any point. The reductions observed in mean values of most comorbidity biomarkers at 6 months were maintained at 12 months. The cohort had improvements in self-reported quality of life and a reduction in depression at 6, 9 and 12 months compared with baseline.
Fewer adverse events in extension phase
About two-thirds of the cohort had an adverse event during the extended phase, with the most common events being arthralgia, headache, hypokalemia and QT prolongation. Of the adverse events reported, 95% were mild or moderate. Serious adverse events were reported in four adults, but none were related to levoketoconazole.
“Levoketoconazole was well tolerated in the extended evaluation phase of the SONICS study,” the researchers wrote. “Overall, the incidence of treatment-emergent adverse events was substantially lower in the extended evaluation phase than in the first two phases of the study, likely a function of common events first occurring early during treatment without subsequent worsening.”
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