An Open Label Study of COR—003 on the treatment of Cushing's syndrome
Research type
Research Study
Full title
An Open Label Study to Assess the Safety and Efficacy of COR—003 (2S, 4R-Ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome
IRAS ID
150294
Contact name
Simon Aylwin
Contact email
Sponsor organisation
Cortendo AB
Eudract number
2013-002133-37
Duration of Study in the UK
2 years, 5 months, 30 days
Research summary
Cortendo AB is developing COR-003, the single 2S,4R enantiomer of ketoconazole, as an investigational new drug for the treatment of cortisol hypersecretion in Endogenous Cushing´s syndrome (CS). CS is a rare but serious and potentially lethal endocrine disease caused by inappropriately excessive cortisol exposure to human organs. Treatment options for CS include surgery, radiation therapy and drug treatment, albeit off-label in most all cases.
It is hypothesized that COR-003 may prove to be both safer and more efficacious than racemic ketoconazole. In vitro studies comparing COR-003 to the other enantiomer of ketoconazole (2R, 4S-ketoconazole) indicate that COR-003 is 10-46 times more potent at multiple sites in the cortisol regulation pathway, i.e., 11ß-hydroxylase, 17a-hydroxylase, and 21a-hydroxylase. Additionally, COR-003 has a significantly lower IC50 to a key enzyme in cholesterol synthesis pathway, (14a-demethylase) versus the other enantiomer potentially yielding a better safety profile. Taken together, the increased cortisol regulation potency and the lesser cholesterol synthesis potency, there is the potential for increased safety and efficacy at lower doses of COR-003 than previously observed with ketoconazole. The in vitro results have been borne out in non-clinical investigations in rats where COR-003 has been shown to be more potent with respect to reducing corticosterone than the other enantiomer or racemic ketoconazole. COR-003 also appeared to reduce cholesterol to a greater extent than the other enantiomer. Lastly, in clinical studies using COR-003 and racemic ketoconazole, COR 003 has demonstrated a dose response reduction in C-reactive protein (CRP) versus racemic ketoconazole showed no reduction in these same studies.
This clinical trial will enroll adult male and female subjects with a confirmed diagnosis of persistent or recurrent CS (with or without therapy) or patients with newly diagnosed disease, if they are not candidates for surgery. The clinical trial is initially planned to be conducted at a total of approximately 38 sites across the US and Europe.
The study is a single arm, open-label, dose titration study to assess efficacy, safety, tolerability and pharmacokinetics of COR-003 in subjects with CS with each subject serving as his/her own control. After titration over 2-16 weeks to a tolerable effective and/or maximum dose (the therapeutic dose), subjects will enter into the maintenance phase of the study and be treated with COR 003 at the therapeutic dose for 6 months. The maintenance phase will be followed by an extended evaluation phase of 6 months continued treatment. Primary efficacy will be assessed by measuring 24-hour urinary free cortisol secretion UFC concentrations at six months.
This clinical trial does not involve the first administration of a new active substance to humans. To date, five clinical studies have been conducted with COR-003: two studies in healthy volunteers and three studies in subjects with Type 2 Diabetes Mellitus.An Investigational Medicinal Product Dossier (IMPD) is provided within this application to support the quality of the COR-003 investigational product.
Scientific advice from the CHMP was sought in the form of protocol assistance and received in February 2013. Scientific advice has also been provided by the US FDA. A copy of the relevant documentation is included within this application.
COR-003 was granted orphan drug designation in Europe for the treatment of Cushing´s syndrome (EU orphan reference EU/3/12/1012). The trial is not being conducted as part of a Paediatric Investigation Plan (PIP).
The documentation included in the submission package is listed below. For the latest clinical trial data, please refer to the Investigator’s Brochure for COR-003, Version 7, 14 October 2013. Reference safety information assessing whether an adverse reaction is a suspected unexpected serious adverse reaction (SUSAR) is contained within in the enclosed Investigator’s Brochure, Section 6. For the overall risk benefit assessment please refer to Section 5.4 of the Investigator’s Brochure for COR-003.REC name
London - City & East Research Ethics Committee
REC reference
14/LO/1514
Date of REC Opinion
17 Nov 2014
REC opinion
Further Information Favourable Opinion