ICEECE2012 Oral Communications Pituitary Clinical I (6 abstracts)
Patients with Cushing’s disease achieve normal urinary cortisol with LCI699, a potent 11β-hydroxylase inhibitor: preliminary results from a multicenter, proof-of-concept study
X. Bertagna 1, , R. Pivonello 3 , M. Fleseriu 4 , Y. Zhang 5 , P. Robinson 6 , A. Taylor 7 , C. Watson 7 , M. Maldonado 8 , A. Hamrahian 9 , M. Boscaro 10 & B. Biller 11
1Cochin Hospital, Paris, France; 2Université Paris 5, Paris, France; 3University of Naples ‘Federico II’, Naples, Italy; 4Northwest Pituitary Center, Oregon Health and Science University, Portland, Oregon, USA; 5Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; 6Novartis Pharmaceuticals UK Limited, Horsham, UK; 7Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA; 8Novartis Pharma AG, Basel, Switzerland; 9Cleveland Clinic Foundation, Cleveland, Ohio, USA; 10Polytechnic University of Marche, Ancona, Italy; 11Massachusetts General Hospital, Boston, Massachusetts, USA.
Introduction: The clinical features and complications of Cushing’s syndrome result from chronic excess of circulating cortisol, typically quantified by 24-h urinary free cortisol (UFC). LCI699 is a potent inhibitor of 11β-hydroxylase. Since 11β-hydroxylase catalyzes the final step of cortisol synthesis, LCI699 is a potential new treatment for all forms of Cushing’s syndrome.
Methods: Adult patients with mild-to-severe Cushing’s disease (UFC>1.5× the upper limit of normal (ULN), mean of three collections in 14 days) received oral LCI699 for 10 weeks in an open-label study. LCI699 was initiated at 2 mg bid. Dose escalation was planned every 2 weeks to 5, 10, 20 and 50 mg bid until UFC normalized, in which case the dose was maintained until day 70, when treatment stopped. Dose reduction for tolerability was permitted. UFC was assessed on the penultimate day of each 2-week period. Patients were monitored until day 84. The primary endpoint was UFC≤ULN or a ≥50% decrease from baseline at day 70 using the mean of 3 UFC samples collected during the week before day 70.
Results: Eleven patients (aged 25–55 years; four men) have been enrolled and nine have completed the study to date. Nine patients had prior surgery. Baseline UFC range was 1.6–17.0×ULN. UFC levels were normal on at least one assessment in 11 of 11 patients during the study. The primary endpoint was achieved by all nine patients who have completed the active treatment phase, eight of whom had normal UFC levels on day 70. After treatment discontinuation, UFC was >ULN in six patients with measurements at day 84. The median dose of LCI699 associated with UFC normalization was between 5 and 10 mg bid. At day 70, mean SBP decreased by 13.1 mmHg from baseline. LCI699 was generally well tolerated; the most frequently reported adverse events were fatigue (5/11), nausea (4/11) and headache (3/11). Five patients experienced ACTH levels >2×baseline. Four patients experienced study drug-related hypokalemia (K+<3.5 mmol/l; min 3.1 mmol/l). There were no serious AEs of suspected drug relationship.
Conclusion: LCI699 demonstrated efficacy with a satisfactory safety profile in this proof-of-concept study in patients with Cushing’s disease.
Declaration of interest: The authors declare that there is a conflict of interest.
Funding: This work was supported, however funding details are unavailable.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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