Strongbridge Biopharma plc Announces Presentation of New Data Demonstrating That Levoketoconazole is a Potent Inhibitor of Human Enzymes Controlling Cortisol Synthesis
~ Data Suggest Levoketoconazole, the Isolated 2S,4R Enantiomer of Ketoconazole,
Accounts for Essentially All of the Inhibition by Ketoconazole of Cortisol Biosynthesis in Humans ~
~ Results Presented at
The study, designed, conducted and presented by Dr.
HEK-293 cells were engineered to stably express the human microsomal enzymes, known as cytochromes P450 or CYPs, 17A1 (17-hydroxylase/17,20-lyase), 21A2 (21-hydroxylase), and 19A1 (aromatase). V79 cells were engineered to stably express the human mitochondrial CYPs 11A1 (side-chain cleavage enzyme), 11B1 (11-hydroxylase), and 11B2 (aldosterone synthase). Enzyme activity was measured in the presence of 2S,4R-ketoconazole, the 2R,4S-isomer, and racemic ketoconazole to generate IC50 (inhibitory potency) values. Additionally, 11A1, 17A1, and 11B1 were expressed in E. coli and purified, and the spectral binding constants (Ks) of racemic ketoconazole and the two enantiomers were determined.
Levoketoconazole was significantly more potent than the 2R,4S-isomer and approximately twice as potent as racemic ketoconazole for CYPs 11A1, 11B1 and 17A1; the potency differences were less marked for CYP 11B2. Ketoconazole or its enantiomers did not inhibit CYPs 19A1 or 21A2 at up to 1000 nanomolar concentration (the highest studied). The degree of potency differences suggests that levoketoconazole accounts for essentially all of the activity of racemic ketoconazole to inhibit cortisol biosynthesis in humans. Spectral binding constants were about three to five times higher than the IC50 for CYPs 17A1 and 11B1 in intact cells, suggesting that, for these enzymes, a second mode of inhibition not involving the canonical binding pockets of these steroidogenic enzymes accounts for a significant portion of the much greater inhibition potency of levoketoconazole as compared with its mirror-opposite isomer 2R,4S-ketoconazole.
RECORLEV™ (levoketoconazole) is an investigational cortisol synthesis inhibitor being evaluated in LOGICS and SONICS, two Phase 3 clinical trials for endogenous Cushing’s syndrome. The safety and efficacy of RECORLEV (levoketoconazole) for the treatment of endogenous Cushing’s syndrome have not been established.
About Strongbridge Biopharma
Strongbridge Biopharma is a global commercial-stage biopharmaceutical company focused on the development and commercialization of therapies for rare diseases with significant unmet needs. Strongbridge's commercial portfolio within its rare neuromuscular and rare endocrine franchises includes KEVEYIS®(dichlorphenamide), the first and only FDA-approved treatment for hyperkalemic, hypokalemic, and related variants of primary periodic paralysis, and MACRILEN™ (macimorelin), the first and only FDA-approved oral drug indicated for the diagnosis of adult growth hormone deficiency. The Company’s rare endocrine franchise also includes a clinical-stage pipeline of therapies: RECORLEV™ (levoketoconazole), a cortisol synthesis inhibitor currently being studied for the treatment of endogenous Cushing's syndrome, and veldoreotide, a next-generation somatostatin analog being investigated for the treatment of acromegaly and potential additional applications in other conditions amenable to somatostatin receptor activation.
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Source: Strongbridge Biopharma plc