Osilodrostat, a potent oral 11β-hydroxylase inhibitor, normalized mean urinary free cortisol (mUFC) in most patients with CD during the 48-week (W) core phase of a Phase III study (LINC3: NCT02180217). We present efficacy and safety results following an extension to LINC3.
CD patients with mUFC > 1.5× upper limit of normal (ULN) received osilodrostat during the core. Patients benefiting from osilodrostat at W48 could enter an extension. Dose adjustments were permitted (maximum dose 30mg bid). LINC3 ended when all ongoing patients had received ≥72 weeks treatment and could enter a separate safety study (results of which are not presented here). Efficacy/safety are reported for all enrolled patients unless otherwise stated. Mean change is calculated for patients with evaluable assessments at core baseline and W72.
106 of 137 enrolled patients entered the extension. Median osilodrostat exposure from core baseline to study end for all enrolled patients was 130 weeks (range, 7245), with a median dose of 7.4mg/day. 98 patients completed W72 and 52 received 33 years of treatment. At W72, 81% (86/106) of patients who entered the extension had mUFC ≤ ULN. Mean mUFC and serum and late-night salivary cortisol levels remained ≤ULN during the extension. Improvements in cardiovascular-related parameters were maintained during the extension; mean (SD) change from core baseline to W72: systolic BP, 10.1 (18.1) mmHg; diastolic BP, 5.8 (11.3) mmHg; HbA1c, 0.4% (0.6); BMI, 1.8 (2.5) kg/m2. AEs related to hypocortisolism and adrenal hormone precursor accumulation, respectively, occurred in 54% (74/137) and 58% (80/137) of patients during the study. Most hypocortisolism-related AEs emerged during the first 26 weeks of treatment. AEs related to adrenal hormone precursor accumulation were less frequent in the extension than the core (occurring in 46%, 19%, 15% and 15% of patients with a safety assessment during the following intervals: baseline‒W26, W26‒48, W48‒72 and W72‒study end). Overall, 32% (34/106) of patients who entered the extension discontinued, most commonly because of AEs or patient/guardian decision (n = 12 each). Median change in tumour volume from core baseline to W72 was 1.0 mm3 (range: ‒74.7 to 1268.5). Mean (SD) 11-deoxycortisol level was stable during the extension (7.4 [6.7] ×ULN at W72). Mean (SD) testosterone level tended to decrease in females during the extension (0.8 [0.7] ×ULN at W72).
Osilodrostat provided long-term control of mUFC in CD patients and improved clinical signs of hypercortisolism and QoL. Osilodrostat was well tolerated, with no new safety signals reported during long-term treatment.
22 May 2021 - 26 May 2021