Endocrine Abstracts

Introduction

The oral 11β-hydroxylase inhibitor, osilodrostat, normalized mean urinary free cortisol (mUFC) in 79% (15/19) of patients with Cushing’s disease at the end of the 22-week core LINC 2 study. Long-term efficacy and safety data following an optional extension phase are reported here.

Methods

Patients with clinical benefit at week 22 could continue receiving osilodrostat during the extension; dose adjustments were permitted based on efficacy/safety. Response status was assessed over time: controlled mUFC (≤ULN) or partially controlled mUFC (>ULN but ≥50% decrease from baseline). Efficacy and safety were assessed for all patients from core baseline to study end.

Results

Of 19 patients enrolled in the core study (female : male 14:5; mean [S.D.] age 36.8 years [8.4]), 16 entered the extension and 8 continued treatment until study end. Median (range) osilodrostat exposure was 282 weeks (2–351). mUFC decreased from 9.9xULN at baseline to ≤ULN by week 4, remaining stable thereafter. At each extension-phase assessment up to month 70, 50–88% of patients had controlled mUFC, and up to 18% were partially controlled. Mean (S.D.) percentage change in clinical signs from baseline to last assessment were: fasting plasma glucose, –10.8% (22.1) (baseline: 105.6 mg/dl [49.2]); HbA_1c, –2.1% (9.0) (baseline: 5.7% [0.7]); systolic BP, –3.3% (12.6) (baseline: 132.6 mmHg [11.6]); diastolic BP, –2.0% (10.4) (baseline: 85.0 mmHg [6.5]); BMI, –5.9% (8.8) (baseline: 30.7 kg/m² [7.0]). Nine patients discontinued treatment, mostly because of AEs or no longer requiring treatment (n = 3 each). The most common AEs during the overall treatment period were nausea (n = 10), adrenal insufficiency, and headache (n = 9 each). AEs related to hypocortisolism and adrenal hormone precursor accumulation occurred in 11 (mostly adrenal insufficiency, n = 9) and 12 patients (mostly hypertension, n = 4), respectively; most were grade 1/2 and managed with dose adjustment/interruption and/or additional therapy. Mean (S.D.) plasma ACTH increased from 1.8xULN (0.9) at baseline to 7.1xULN (12.3) at week 22 and 6.9xULN (12.6) at last assessment. Mean (S.D.) 11-deoxycortisol increased from 1.2xULN (1.3) at baseline to 13.6xULN (12.2) at week 22 and 3.6xULN (4.2) at last assessment. In females, mean (S.D.) testosterone increased from 0.8xULN (0.4) at baseline to 2.4xULN (2.1) at week 22 and 1.0xULN (0.9) at last assessment. AEs of hirsutism were reported in two female patients.

Conclusions

Osilodrostat provided rapid and sustained reductions in mUFC for up to 6 years of treatment, with improvements in clinical signs of hypercortisolism. Osilodrostat was well tolerated, with no new safety signals during long-term treatment.