ECE2020 Audio ePoster Presentations Pituitary and Neuroendocrinology (217 abstracts)
Background: The phase 3, open-label SONICS study of levoketoconazole demonstrated sustained reduction in mean urinary free cortisol (mUFC) in adults with endogenous Cushing’s syndrome (CS). The extended evaluation phase (Ext) of SONICS reported here further assessed long-term safety, tolerability, and benefit/risk of this treatment.
Methods: SONICS consisted of dose-titration (150 – 600 mg BID to attain maximally tolerated dose for mUFC normalization), 6-month maintenance, and 6-month Ext phases. Safety and efficacy evaluations occurred at Month 9 (M9) and Month 12 (M12) in Ext. Potential liver toxicity, QTc prolongation, and adrenal insufficiency were prespecified AEs of special interest. Exploratory efficacy assessments included mUFC response, changes in CS clinical signs and symptoms, quality-of-life (Cushing QoL score), and symptoms of depression (BDI-II score) from baseline to M9 and M12. Serum ACTH levels were assessed in those with Cushing’s disease. The concentration-response relationship of levoketoconazole and mUFC levels was assessed. Treatment adherence was defined as ≥80–120% intake of the study drug.
Results: 94 patients were enrolled and treated with ≥1 levoketoconazole dose; 77 patients entered and 61 completed the maintenance phase. 60 patients entered and 46 completed Ext. The most common incident AEs in Ext (n = 60) were arthralgia (6.7%), headache (6.7%), hypokalemia (6.7%), QTc prolongation (6.7%), and nasopharyngitis (5.0%). AEs led to study discontinuation in Ext in 4 (6.7%) patients. No patients experienced increased ALT or AST > 3 × ULN, had suspected adrenal insufficiency, or had QTcF interval of >460 msec in Ext. Serious AEs were reported in 4 patients during Ext, but none were considered levoketoconazole-related. 27 of 49 (55.1%) and 18 of 44 (40.9%) patients had normalized mUFC at M9 and M12, respectively. Concentration-response modeling indicated no evidence for tolerance to (ie, ‘escape’ from) mUFC reduction. Furthermore, mean ACTH levels at M9 and M12 were similar in those with (n = 15) and without (n = 21) mUFC normalization at M12. Treatment adherence was reduced at M12 (82.0%) relative to M9 (91.4%), likely accounting for the decreased mUFC normalization rate at M12. Mean improvements from baseline in CS clinical signs and symptoms (acne, hirsutism, and peripheral oedema scores), and Cushing’s QoL and BDI-II scores observed following 6 months of maintenance phase were generally maintained at M9 and M12.
Conclusions: In the SONICS study Ext, levoketoconazole was well tolerated with no new drug-related safety signals observed. Sustained mUFC response and improvements in CS clinical signs and symptoms, quality-of-life, and symptoms of depression were demonstrated in those completing Ext.
05 Sep 2020 - 09 Sep 2020