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Clinical Trial
. 2016 Apr;19(2):138-48.
doi: 10.1007/s11102-015-0692-z.

Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing's disease

Maria Fleseriu  1 , Rosario Pivonello  2 , Jacques Young  3 , Amir H Hamrahian  4 , Mark E Molitch  5 , Chikara Shimizu  6 , Tomoaki Tanaka  7 , Akira Shimatsu  8 , Tracy White  9 , Annie Hilliard  9 , Chuan Tian  9 , Nicholas Sauter  9 , Beverly M K Biller  10 , Xavier Bertagna  11
Affiliations
Clinical Trial

Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing's disease

Maria Fleseriu et al. Pituitary. 2016 Apr.

Abstract

Purpose: In a 10-week proof-of-concept study (LINC 1), the potent oral 11β-hydroxylase inhibitor osilodrostat (LCI699) normalized urinary free cortisol (UFC) in 11/12 patients with Cushing's disease. The current 22-week study (LINC 2; NCT01331239) further evaluated osilodrostat in patients with Cushing's disease.

Methods: Phase II, open-label, prospective study of two patient cohorts. Follow-up cohort: 4/12 patients previously enrolled in LINC 1, offered re-enrollment if baseline mean UFC was above ULN. Expansion cohort: 15 newly enrolled patients with baseline UFC > 1.5 × ULN. In the follow-up cohort, patients initiated osilodrostat twice daily at the penultimate efficacious/tolerable dose in LINC 1; dose was adjusted as needed. In the expansion cohort, osilodrostat was initiated at 4 mg/day (10 mg/day if baseline UFC > 3 × ULN), with dose escalated every 2 weeks to 10, 20, 40, and 60 mg/day until UFC ≤ ULN. Main efficacy endpoint was the proportion of responders (UFC ≤ ULN or ≥50% decrease from baseline) at weeks 10 and 22.

Results: Overall response rate was 89.5% (n/N = 17/19) at 10 weeks and 78.9% (n/N = 15/19) at 22 weeks; at week 22, all responding patients had UFC ≤ ULN. The most common AEs observed during osilodrostat treatment were nausea, diarrhea, asthenia, and adrenal insufficiency (n = 6 for each). New or worsening hirsutism (n = 2) and/or acne (n = 3) were reported among four female patients, all of whom had increased testosterone levels.

Conclusions: Osilodrostat treatment reduced UFC in all patients; 78.9% (n/N = 15/19) had normal UFC at week 22. Treatment with osilodrostat was generally well tolerated.

Keywords: 11β-hydroxylase; Cortisol; Cushing’s; LCI699; Osilodrostat.

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Figures

Fig. 1
Fig. 1
Study design and dosing schedule
Fig. 2
Fig. 2
Absolute change in UFC from baseline in the 17 patients who completed 22 weeks (safety analysis set). Normal range: 11–138 nmol/24 h
Fig. 3
Fig. 3
a UFC, b morning serum cortisol, c morning salivary cortisol, and d late-night salivary cortisol levels over time during osilodrostat treatment, by cohort (safety analysis set). All data are mean ± SE (standard error). Normal ranges are as follows: UFC, 11–138 nmol/24 h; morning serum cortisol, 127–567 nmol/L; morning salivary cortisol, 1.1–15.5 nmol/L; late-night salivary cortisol, ≤2.5 nmol/L
Fig. 4
Fig. 4
Hormone levels at baseline, week 10, and week 22, by cohort (safety analysis set). Asterisk indicated ULN is for females. All data are mean + SD. Normal ranges are as follows: ACTH, 1.8–9.2 pmol/L; 11-deoxycortisol, 0–3.92 nmol/L; 11-deoxycorticosterone, 0.12–0.35 nmol/L (males) and 0.05–0.39 nmol/L (females); renin, not available; aldosterone, 55–250 pmol/L
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