Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushing's syndrome

Abstract

Purpose: The efficacy of levoketoconazole in treating hypercortisolism was demonstrated in an open-label phase 3 study (SONICS) of adults with endogenous Cushing's syndrome (CS) and baseline mean urinary free cortisol (mUFC) ≥ 1.5× ULN. Clinical signs and symptoms and patient-reported outcomes from the SONICS trial were evaluated in the current manuscript.

Methods: Patients titrated to an individualized therapeutic dose entered a 6-month maintenance phase. Secondary endpoints included investigator-graded clinical signs and symptoms of CS during the maintenance phase, and patient-reported quality of life (CushingQoL questionnaire) and depression symptoms (Beck Depression Inventory II [BDI-II]).

Results: Of 94 enrolled patients, 77 entered the maintenance phase following individualized dose titration. Significant mean improvements from baseline were noted at end of maintenance (Month 6) for acne, hirsutism (females only), and peripheral edema. These improvements were observed as early as Day 1 of maintenance for hirsutism (mean baseline score, 7.8; ∆ - 1.9; P < 0.0001), end of Month 1 for acne (mean baseline score, 2.8; ∆ - 1.2; P = 0.0481), and Month 4 for peripheral edema (mean baseline score, 1.0; ∆ - 0.5; P = 0.0052). Significant mean improvements from baseline were observed by Month 3 of maintenance for CushingQoL (mean baseline score, 44.3; ∆ + 6.9; P = 0.0018) and at Month 6 for BDI-II (mean baseline score, 17.1; ∆ - 4.3; P = 0.0043) scores. No significant mean improvement was identified in a composite score of 7 other clinical signs and symptoms.

Conclusions: Treatment with levoketoconazole was associated with sustained, meaningful improvements in QoL, depression, and certain clinical signs and symptoms characteristic of CS. ClinialTrials.gov identifier: NCT01838551.

Keywords: Cushing’s disease; Cushing’s syndrome; Hypercortisolism; Quality of life; Steroidogenesis inhibitor.

Conflict of interest statement

EBG reports serving as an investigator for research grants to MSKCC from Ionis, Novartis, Corcept, and Strongbridge Biopharma. RS reports serving as the principal investigator of research grants to Johns Hopkins University from Novartis, Corcept, Crinetics, and Strongbridge Biopharma; and receiving consulting honoraria from Novo Nordisk. AE reports serving as the principal investigator/sub-investigator of clinical trials for Corcept Therapeutics and Novartis and receiving consulting honoraria from Novartis. MF reports serving as an investigator with research grants to OHSU for Millendo, Novartis, and Strongbridge Biopharma; and serving as an occasional consultant to Novartis and Strongbridge Biopharma. RP reports serving as the principal investigator of research grants to Federico II University from Corcept Therapeutics, Novartis, and Strongbridge Biopharma; and receiving consulting honoraria from Novartis and Strongbridge Biopharma. PW reports receiving travel grants from Ipsen and Novartis; and receiving personal fees as a clinical investigator from Ipsen, Novartis, Novo Nordisk, and Strongbridge Biopharma. RAF reports receiving research grants from Novartis; and serving on the speakers’ bureau for HRA Pharma and Novartis. MB reports receiving research grants from Strongbridge Biopharma. SWB reports no conflicts of interest. SP reports receiving research grants from HRA Pharma. BMKB reports serving as the principal investigator of research grants to Massachusetts General Hospital from Millendo, Novartis, and Strongbridge Biopharma; and serving as an occasional consultant to Novartis and Strongbridge Biopharma. FC reports being an employee of Strongbridge Biopharma. FPG reports receiving consulting honoraria from Novartis, HRA Pharma, and IBI-Lorenzini.

Figures

Fig. 1

Study design. D day, EoM end of maintenance, M month, mUFC mean urinary free cortisol, UFC urinary free cortisol, ULN upper limit of normal. aAll patients started at the protocol-mandated dose of 150 mg twice daily, but a reduction to 150 mg once daily to improve tolerability was allowed. bA therapeutic dose was considered established when 1) mUFC was normalized (i.e., ≤ ULN) or 2) levoketoconazole dose of 600 mg twice daily or a maximal tolerated dose was reached and there was a clinically meaningful partial response in the opinion of the investigator

Fig. 2

Mean scores for clinical signs and symptoms of Cushing’s syndrome from baseline through the end of the maintenance phase for a acne global score, b hirsutism total score (females), c peripheral edema total score, and d total score for 7 other signs and symptoms (maintenance population). Two-sided P value from the paired t-test that was performed on the mean change from baseline to each timepoint. Acne global score could range from 0 to 44, where 0 = none, 1–18 = mild, 19–30 = moderate, 31–38 = severe, and ≥39 = very severe. Hirsutism total score could range from 0 (none) to 36 (worst). Peripheral edema total score could range from 0 (none) to 12 (worst). Seven other signs or symptoms (moon facies, facial plethora, striae, bruising, supraclavicular fat, irregular menstruation [females only], dysmenorrhea [females only]) were rated by investigators on a scale from 0 to 3, for which 0 = absent, 1 = mild, 2 = moderate, and 3 = severe (total score range, 0–21). As only 5 of these 7 signs and symptoms apply to males, their total score was multiplied by 7 and divided by 5 in order to standardize the score for both sexes. SEM standard error of the mean. *P < 0.05; †P < 0.01; ‡P < 0.001

Fig. 3

Improvement, no change, or worsening in clinical signs and symptoms of Cushing’s syndrome, based on categorical shift in item score (maintenance population). Improvement was assessed in patients with signs or symptoms at baseline (baseline score ≠ 0) and worsening was assessed in patients with absent or less than severe signs or symptoms at baseline (baseline score

Fig. 4

Mean scores from baseline through the end of the maintenance phase for CushingQoL total score (maintenance population). Two-sided P value from the paired t-test that was performed on the mean change from baseline to each timepoint. CushingQoL score could range from 0 (worst) to 100 (best). QoL quality of life, SEM standard error of the mean. *P < 0.01 versus baseline; †P < 0.001 versus baseline

Fig. 5

Beck Depression Inventory II total score. a Mean scores from baseline through the end of the maintenance phase for BDI-II total score (maintenance population).a Two-sided P value from the paired t-test that was performed on the mean change from baseline to each timepoint. BDI-II total score could range from 0 (best) to 63 (worst), with depression severity considered minimal for a score of 0–13, mild for 14–19, moderate for 20–28, and severe for 29–63; thus, a decrease in score reflects clinical improvement. b Categorical shifts in BDI-II total score from baseline to Months 3 and 6 of the maintenance phase (maintenance population). Dashed lines identify patient group for which the baseline category was unchanged at postbaseline assessment. BDI-II Beck Depression Inventory II, SEM standard error of the mean. aAs BDI-II was added as an outcome after study initiation, BDI-II data are not available for early recruited patients. *P < 0.01

Fig. 6

Mean free testosterone levels from baseline through the end of the maintenance phase in a males and b females (maintenance population). Two-sided P value from the paired t-test that was performed on the mean change from baseline to each timepoint. Free testosterone reference levels: males aged 18–69 years, 4.6–22.4 ng/dL (0.160–0.777 nmol/L); males aged 70–89 years, 0.6–7.3 ng/dL (0.021–0.253 nmol/L); females aged 18–69 years, 0.02–0.5 ng/dL (0.0007–0.017 nmol/L); females aged 70–89 years, 0.03–0.5 ng/dL (0.001–0.017 nmol/L). SEM standard error of the mean. *P < 0.0001