6591 Effects of Levoketoconazole on 24-hour Mean UFC (mUFC) in the SONICS Study: Relation to Baseline mUFC in Adults with Cushing’s Syndrome: a Post-hoc Analysis

Abstract Disclosure: R. Huang: Employee; Self; Xeris Pharmaceuticals. D. Harper: Employee; Self; Xeris Pharmaceuticals. J. Meyer: Employee; Self; Xeris Pharmaceuticals. F.M. Cohen: Consulting Fee; Self; Xeris Pharmaceuticals. Background: Prior exploratory analyses of the open-label, non-randomized, single-arm Phase 3 SONICS study of levoketoconazole suggested that the mUFC response rate at 6 months varied by baseline mUFC stratum. That exploration focused on the subset of the study population that had completed Dose-Titration phase and advanced into the 6-month Maintenance phase. We now expand this exploration to include all enrolled patients in SONICS who were treated and had a postbaseline mUFC, aiming to further elucidate relationships between baseline biochemical disease severity, drug dose, and intermediate-term mUFC response. Methods: 94 adults with confirmed Cushing’s syndrome were enrolled to receive levoketoconazole treatment at a starting dose of 150 mg BID, titrated as needed at 150 mg intervals until a maximum dose of 600 mg BID or an adequate response was achieved in the investigator’s judgment. Following Dose-Titration phase, eligible patients immediately entered a Maintenance phase of approximately 6 months, during which the dose could be changed only to regain biochemical control or for safety reasons. The primary endpoint was the proportion of patients in the ITT population with mUFC normalization at end of the 6-month Maintenance phase, without a dose increase during maintenance. For the current analyses, 92 patients treated with levoketoconazole and with baseline mUFC measurement (modified ITT) were stratified into 3 baseline mUFC subgroups—Group 1: 1.5x to ≤2.5x upper limit of normal (ULN); Group 2: >2.5x to ≤5x ULN; Group 3: >5x ULN and analyzed with respect to mUFC response, average daily dose, and adverse events following 6 months of Maintenance therapy. Results: Group 2 had the highest apparent mUFC response rate (12/33 [36.4%]); 95% CI 0.20, 0.54) as compared with Group 1 (12/38 [31.6%]; 95% CI 0.16, 0.47) or Group 3 (5/21 [23.8%]; 95% CI 0.01, 0.55); Group 3 having a notably lower response. Daily doses of levoketoconazole were related to baseline mUFC. Thus, Group 3 used a nominally higher average daily dose during Maintenance therapy and at the end of the 6-month Maintenance phase (680 mg and 741 mg) than Group 1 (508 mg and 566 mg) or Group 2 (617 mg and 611 mg). Group 3 had more liver-related adverse events of special interest than Group 1 or 2 (14% vs 7.9% or 3.0%) and more AEs leading to discontinuation (24% vs 12% or 16%). Conclusion: In this post-hoc analysis, lower mUFC at baseline predicted the likelihood of achieving mUFC normalization following 6 months of levoketoconazole Maintenance therapy and was associated with lower Maintenance dose requirements and lower rates of potentially clinically important liver-related AEs. Presentation: 6/1/2024