Long-term outcomes of osilodrostat in Cushing's disease: LINC 3 study extension

Abstract

Objective: To investigate the long-term efficacy and tolerability of osilodrostat, a potent oral 11β-hydroxylase inhibitor, for treating Cushing's disease (CD).

Design/methods: A total of 137 adults with CD and mean 24-h urinary free cortisol (mUFC) > 1.5 × upper limit of normal (ULN) received osilodrostat (starting dose 2 mg bid; maximum 30 mg bid) during the prospective, Phase III, 48-week LINC 3 (NCT02180217) core study. Patients benefiting from osilodrostat at week 48 could enter the optional extension (ending when all patients had received ≥ 72 weeks of treatment or discontinued). Efficacy and safety were assessed for all enrolled patients from the core study baseline.

Results: Median osilodrostat exposure from the core study baseline to study end was 130 weeks (range 1-245) and median average dose was 7.4 mg/day (range 0.8-46.6). The reduction in mean mUFC achieved during the core was maintained during the extension and remained ≤ ULN. Of 106 patients, 86 (81%) patients who entered the extension had mUFC ≤ ULN at week 72. Improvements in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism (fat pads, central obesity, rubor, striae, and hirsutism in females), and quality of life in the core study were also maintained or improved further during the extension. No new safety signals were reported; 15/137 (10.9%) and 12/106 (11.3%) patients discontinued for adverse events during the core and extension, respectively. Mean testosterone in females decreased towards baseline levels during the extension.

Conclusions: Data from this large, multicentre trial show that long-term treatment with osilodrostat sustains cortisol normalisation alongside clinical benefits in most patients with CD and is well tolerated.

Figure 1

Patient disposition. *Both deaths were assessed as unrelated to osilodrostat: one case of fatal viral gastroenteritis with cardiopulmonary failure and one suicide; ^†Please see references.

Figure 2

(A) Mean (+s.d.) mUFC and median (IQR) osilodrostat dose over time; (B) individual patient changes in mUFC from baseline to week 72. Shaded area in (A) indicates the core phase. The average osilodrostat total daily dose at visit X was calculated as the average of the osilodrostat total daily dose on each day between visit X and the previous visit. The reference line is the ULN of mUFC, 138 nmol/24 h.

Figure 3

Mean (+s.d.) (A) morning serum cortisol and (B) LNSC during the study. Shaded areas indicate the core phase. This analysis includes scheduled visits only. n is the number of patients who contributed to the mean. Reference lines indicate the LLN and ULN for morning serum cortisol of 127 and 567 nmol/L, respectively, and the ULN for LNSC of 2.5 nmol/L. Different durations of follow-up are shown for serum morning cortisol and LNSC to display the longest possible duration over which data were collected.

Figure 4

Proportion of patients with an improvement from baseline in physical manifestations of hypercortisolism over time. Shaded area indicates the core phase. An improvement was defined as the symptom score being lower (i.e. less severe) than at baseline. The denominator for the percentage is the number of patients in the full analysis set (all enrolled patients who received at least one dose of osilodrostat; shown in brackets for female patients assessed for hirsutism), with data available at both baseline and the given visit. n = 105 at week 24 for facial rubor.

Figure 5

Occurrence of AEs of special interest by time interval. Shaded area indicates the core phase. n is the number of patients with ≥1 scheduled visit or AE during the time interval. *Maximum exposure 245 weeks.

Figure 6

Mean (+s.d.) hormone levels up to the last observed value in the extension phase for (A) ACTH, (B) 11-deoxycortisol, (C) 11-deoxycorticosterone, (D) aldosterone, (E) renin, (F) DHEAS, (G) oestradiol, and (H) oestrone. ACTH normal range: 1.6–11.1 pmol/L in males and 1.1–6.0 pmol/L in females; 11-deoxycortisol ULN, 3.9 nmol/L in males and 3.1 nmol/L in females, or lower depending on age; 11-deoxycorticosterone ULN, 455 pmol/L in males and 696 pmol/L in females (mid-cycle); plasma aldosterone ULN, 777 pmol/L (upright, 08:00‒10:00); DHEAS ULN, 18.8 µmol/L in males and 10.6 μmol/L in females, or lower depending on age; renin ULN, 46.1 mU/L; serum oestradiol ULN, 106 pmol/L in males and 2797 pmol/L in females (mid-cycle); oestrone ULN, 255 pmol/L in males and 991 pmol/L in females (mid-cycle). F, female; M, male.

Figure 7

Mean (+s.d.) testosterone levels in males and females. Testosterone reference range: 8.4–28.7 nmol/L (males), 0.7–2.6 nmol/L (females). Shaded area indicates the core phase. Different durations of follow-up are shown to display the longest possible duration over which data were collected.