LCI699, a Potent 11β-hydroxylase Inhibitor, normalizes urinary cortisol in patients with Cushing's disease: Results from a multicenter, proof-of-concept study

Xavier Bertagna, Rosario Pivonello, Maria Fleseriu, Yiming Zhang, Paul Robinson, Ann Taylor, Catherine E. Watson, Mario Maldonado, Amir H. Hamrahian, Marco Boscaro, Beverly M K Biller

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Introduction: The clinical features and increased mortality associated with Cushing's syndrome result from a chronic excess of circulating cortisol. As LCI699 potently inhibits 11β-hydroxylase, which catalyzes the final step of cortisol synthesis, it is a potential new treatment for Cushing's disease, the most common cause of endogenous Cushing's syndrome. Methods: Adult patients with moderate-to-severe Cushing's disease (urinary free cortisol [UFC] levels >1.5 X ULN [upper limit of normal]) received oral LCI699 for 10 weeks in this proof-ofconcept study. LCI699 was initiated at 4 mg/d in two equal doses; the dose was escalated every 14 days to 10, 20, 40, and 100 mg/d until UFC normalized, whereupon the dose was maintained until treatment ended (day 70). The primary endpoint was UFC≤ULN or a≥50% decrease from baseline at day 70. Results: Twelve patients were enrolled and completed the study. Baseline UFC ranged over 1.6 - 17.0 X ULN. All 12 patients achieved UFC ≤ ULN or a≥50% decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. After treatment discontinuation (day 84), UFC was >ULN in 10 patients with available measurements. Mean 11-deoxycortisol, 11-deoxycorticosterone, and adrenocorticotropic hormone levels increased during treatment and declined after discontinuation. Mean systolic and diastolic blood pressure decreased from baseline by 10.0 and 6.0 mmHg, respectively. LCI699 was generally well tolerated; most adverse events (AEs) were mild or moderate. The most common AEs included fatigue (7/12), nausea (5/12), and headache (3/12). No serious drug-related AEs were reported. Conclusions: LCI699 was efficacious and well tolerated in patients with Cushing's disease enrolled in this proof-of-concept study.

Original languageEnglish (US)
Pages (from-to)1375-1383
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number4
DOIs
StatePublished - 2014

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Pituitary ACTH Hypersecretion
Mixed Function Oxygenases
Hydrocortisone
Cushing Syndrome
Cortodoxone
Blood Pressure
Desoxycorticosterone
LCI699
Blood pressure
Therapeutics
Drug-Related Side Effects and Adverse Reactions
Adrenocorticotropic Hormone
Nausea
Fatigue
Headache
Fatigue of materials
Mortality

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

LCI699, a Potent 11β-hydroxylase Inhibitor, normalizes urinary cortisol in patients with Cushing's disease : Results from a multicenter, proof-of-concept study. / Bertagna, Xavier; Pivonello, Rosario; Fleseriu, Maria; Zhang, Yiming; Robinson, Paul; Taylor, Ann; Watson, Catherine E.; Maldonado, Mario; Hamrahian, Amir H.; Boscaro, Marco; Biller, Beverly M K.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 99, No. 4, 2014, p. 1375-1383.

Research output: Contribution to journalArticle

Bertagna, Xavier ; Pivonello, Rosario ; Fleseriu, Maria ; Zhang, Yiming ; Robinson, Paul ; Taylor, Ann ; Watson, Catherine E. ; Maldonado, Mario ; Hamrahian, Amir H. ; Boscaro, Marco ; Biller, Beverly M K. / LCI699, a Potent 11β-hydroxylase Inhibitor, normalizes urinary cortisol in patients with Cushing's disease : Results from a multicenter, proof-of-concept study. In: Journal of Clinical Endocrinology and Metabolism. 2014 ; Vol. 99, No. 4. pp. 1375-1383.
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abstract = "Introduction: The clinical features and increased mortality associated with Cushing's syndrome result from a chronic excess of circulating cortisol. As LCI699 potently inhibits 11β-hydroxylase, which catalyzes the final step of cortisol synthesis, it is a potential new treatment for Cushing's disease, the most common cause of endogenous Cushing's syndrome. Methods: Adult patients with moderate-to-severe Cushing's disease (urinary free cortisol [UFC] levels >1.5 X ULN [upper limit of normal]) received oral LCI699 for 10 weeks in this proof-ofconcept study. LCI699 was initiated at 4 mg/d in two equal doses; the dose was escalated every 14 days to 10, 20, 40, and 100 mg/d until UFC normalized, whereupon the dose was maintained until treatment ended (day 70). The primary endpoint was UFC≤ULN or a≥50{\%} decrease from baseline at day 70. Results: Twelve patients were enrolled and completed the study. Baseline UFC ranged over 1.6 - 17.0 X ULN. All 12 patients achieved UFC ≤ ULN or a≥50{\%} decrease from baseline at day 70; 11 (92{\%}) had normal UFC levels at that time. After treatment discontinuation (day 84), UFC was >ULN in 10 patients with available measurements. Mean 11-deoxycortisol, 11-deoxycorticosterone, and adrenocorticotropic hormone levels increased during treatment and declined after discontinuation. Mean systolic and diastolic blood pressure decreased from baseline by 10.0 and 6.0 mmHg, respectively. LCI699 was generally well tolerated; most adverse events (AEs) were mild or moderate. The most common AEs included fatigue (7/12), nausea (5/12), and headache (3/12). No serious drug-related AEs were reported. Conclusions: LCI699 was efficacious and well tolerated in patients with Cushing's disease enrolled in this proof-of-concept study.",
author = "Xavier Bertagna and Rosario Pivonello and Maria Fleseriu and Yiming Zhang and Paul Robinson and Ann Taylor and Watson, {Catherine E.} and Mario Maldonado and Hamrahian, {Amir H.} and Marco Boscaro and Biller, {Beverly M K}",
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T1 - LCI699, a Potent 11β-hydroxylase Inhibitor, normalizes urinary cortisol in patients with Cushing's disease

T2 - Results from a multicenter, proof-of-concept study

AU - Bertagna, Xavier

AU - Pivonello, Rosario

AU - Fleseriu, Maria

AU - Zhang, Yiming

AU - Robinson, Paul

AU - Taylor, Ann

AU - Watson, Catherine E.

AU - Maldonado, Mario

AU - Hamrahian, Amir H.

AU - Boscaro, Marco

AU - Biller, Beverly M K

PY - 2014

Y1 - 2014

N2 - Introduction: The clinical features and increased mortality associated with Cushing's syndrome result from a chronic excess of circulating cortisol. As LCI699 potently inhibits 11β-hydroxylase, which catalyzes the final step of cortisol synthesis, it is a potential new treatment for Cushing's disease, the most common cause of endogenous Cushing's syndrome. Methods: Adult patients with moderate-to-severe Cushing's disease (urinary free cortisol [UFC] levels >1.5 X ULN [upper limit of normal]) received oral LCI699 for 10 weeks in this proof-ofconcept study. LCI699 was initiated at 4 mg/d in two equal doses; the dose was escalated every 14 days to 10, 20, 40, and 100 mg/d until UFC normalized, whereupon the dose was maintained until treatment ended (day 70). The primary endpoint was UFC≤ULN or a≥50% decrease from baseline at day 70. Results: Twelve patients were enrolled and completed the study. Baseline UFC ranged over 1.6 - 17.0 X ULN. All 12 patients achieved UFC ≤ ULN or a≥50% decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. After treatment discontinuation (day 84), UFC was >ULN in 10 patients with available measurements. Mean 11-deoxycortisol, 11-deoxycorticosterone, and adrenocorticotropic hormone levels increased during treatment and declined after discontinuation. Mean systolic and diastolic blood pressure decreased from baseline by 10.0 and 6.0 mmHg, respectively. LCI699 was generally well tolerated; most adverse events (AEs) were mild or moderate. The most common AEs included fatigue (7/12), nausea (5/12), and headache (3/12). No serious drug-related AEs were reported. Conclusions: LCI699 was efficacious and well tolerated in patients with Cushing's disease enrolled in this proof-of-concept study.

AB - Introduction: The clinical features and increased mortality associated with Cushing's syndrome result from a chronic excess of circulating cortisol. As LCI699 potently inhibits 11β-hydroxylase, which catalyzes the final step of cortisol synthesis, it is a potential new treatment for Cushing's disease, the most common cause of endogenous Cushing's syndrome. Methods: Adult patients with moderate-to-severe Cushing's disease (urinary free cortisol [UFC] levels >1.5 X ULN [upper limit of normal]) received oral LCI699 for 10 weeks in this proof-ofconcept study. LCI699 was initiated at 4 mg/d in two equal doses; the dose was escalated every 14 days to 10, 20, 40, and 100 mg/d until UFC normalized, whereupon the dose was maintained until treatment ended (day 70). The primary endpoint was UFC≤ULN or a≥50% decrease from baseline at day 70. Results: Twelve patients were enrolled and completed the study. Baseline UFC ranged over 1.6 - 17.0 X ULN. All 12 patients achieved UFC ≤ ULN or a≥50% decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. After treatment discontinuation (day 84), UFC was >ULN in 10 patients with available measurements. Mean 11-deoxycortisol, 11-deoxycorticosterone, and adrenocorticotropic hormone levels increased during treatment and declined after discontinuation. Mean systolic and diastolic blood pressure decreased from baseline by 10.0 and 6.0 mmHg, respectively. LCI699 was generally well tolerated; most adverse events (AEs) were mild or moderate. The most common AEs included fatigue (7/12), nausea (5/12), and headache (3/12). No serious drug-related AEs were reported. Conclusions: LCI699 was efficacious and well tolerated in patients with Cushing's disease enrolled in this proof-of-concept study.

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