Levoketoconazole in the Treatment of Patients With Cushing’s Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study

Abstract

BackgroundCushing’s syndrome (CS) is associated with numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole, an orally administered ketoconazole stereoisomer, is in clinical trials for the treatment of CS.MethodsSONICS, a prospective, open-label, phase 3 study in adults with confirmed CS and mean 24-h urinary free cortisol (mUFC) ≥1.5× ULN, included dose-titration, 6-month maintenance, and 6-month extension phases. This subanalysis evaluated the efficacy of levoketoconazole in patients with DM (n = 28) or without DM (n = 49) who entered the maintenance phase. Safety was evaluated in the overall population (N = 94) during the dose-titration and maintenance phases.ResultsNormalization of mUFC at the end of maintenance phase (EoM), without a dose increase during maintenance (SONICS primary endpoint) was observed in 46% of patients with DM (95% CI, 28 to 66%; P = 0.0006 vs null hypothesis of ≤20%) and 33% of patients without DM (95% CI, 20 to 48%; P = 0.0209). At EoM, mean HbA1c decreased from 6.9% at baseline to 6.2% in patients with DM and from 5.5 to 5.3% in patients without DM. Mean fasting blood glucose decreased from 6.85 mmol/L (123.4 mg/dl) to 5.82 mmol/L (104.9 mg/dl) and from 5.11 mmol/L (92.1 mg/dl) to 4.66 mmol/L (84.0 mg/dl) in patients with and without DM, respectively. Adverse events that were more common in patients with DM included nausea (58.3%), vomiting (19.4%), and urinary tract infection (16.7%); none prompted study drug withdrawal.ConclusionsTreatment with levoketoconazole led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with DM.Clinical Trial Registration(ClinicalTrials.gov), NCT01838551.

Levoketoconazole: a novel treatment for endogenous Cushing's syndrome

“…At the end of the maintenance phase, normalization of mUFC was observed in 34% and 25% of patients with and without diabetes mellitus, respectively, without a dose increase during the maintenance phase. In addition, the measures of glycemic control, HbA1c and fasting blood glucose levels, were improved in both subgroups, but change was more pronounced in patients with diabetes mellitus (Figure 5) [71].…”

“…Normalization of cortisol is sufficient, in some cases, to improve glycemic control and may also reverse diabetes [2,70]. In SONICS, efficacy and safety of levoketoconazole in patients with CS and diabetes mellitus (36 patients) were evaluated as exploratory analyses [71]. At the end of the maintenance phase, normalization of mUFC was observed in 34% and 25% of patients with and without diabetes mellitus, respectively, without a dose increase during the maintenance phase.…”

Levoketoconazole

“…A subgroup analysis of patients with diabetes mellitus showed mean UFC normalization with levoketoconazole was similar in patients with and without diabetes mellitus; some patients were able to lower the dose of their diabetes medication(s); and improvements were observed in LDL-C, weight, body mass index, and waist circumference. 16,17…”

Management and Medical Therapy of Mild Hypercortisolism

“…On the basis of these promising results on glucose metabolism, levoKTZ was studied in 94 patients affected by CS in a phase III, open-label, multicenter clinical trial (SONICS study), which found UFC normalization in 46% and 33% of patients with diabetes mellitus and without diabetes mellitus, respectively. Interestingly, in diabetic patients, who were adequately controlled at baseline, levoKTZ treatment led to a clear amelioration of glycometabolic control (i.e., glycated hemoglobin decreased from 6.9% to 6.2%), and a decrease in glycated hemoglobin (i.e., from 5.5% to 5.3%) was noted even in non-diabetic patients [ 94 ]. In addition, after the 6-month maintenance period, a significant decrease in body weight, peripheral edema and acne and hirsutism in women as well as an improvement in quality of life and depressive status was observed [ 94 , 95 ].…”

“…Interestingly, in diabetic patients, who were adequately controlled at baseline, levoKTZ treatment led to a clear amelioration of glycometabolic control (i.e., glycated hemoglobin decreased from 6.9% to 6.2%), and a decrease in glycated hemoglobin (i.e., from 5.5% to 5.3%) was noted even in non-diabetic patients [ 94 ]. In addition, after the 6-month maintenance period, a significant decrease in body weight, peripheral edema and acne and hirsutism in women as well as an improvement in quality of life and depressive status was observed [ 94 , 95 ]. These data now need to be confirmed in the phase III, double-blind, multicenter clinical trial (LOGICS study) that was started in September 2017 to assess the efficacy and safety of levoKTZ treatment in CS patients, of which no preliminary data have been available so far ( ; accessed date: 21 October 2021).…”