~ 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 ENDO 2018, the Annual Meeting of the Endocrine Society ~
DUBLIN, Ireland and TREVOSE, Pa., March 18, 2018 (GLOBE NEWSWIRE) — Strongbridge Biopharma plc, (Nasdaq:SBBP), a global commercial-stage biopharmaceutical company focused on the development and commercialization of therapies for rare diseases with significant unmet needs, announced that results from an in vitro study of levoketoconazole, the active ingredient in RECORLEV™, were presented at ENDO 2018, the Annual Meeting of the Endocrine Society, taking place in Chicago, Illinois from March 17 – 20, 2018.
The study, designed, conducted and presented by Dr. Richard Auchus and colleagues from the University of Michigan School of Medicine, aimed to characterize the potency and mechanism(s) of 2S,4R-ketoconazole (levoketoconazole, the active ingredient of RECORLEV) inhibition of human steroidogenic enzymes in intact cells in vitro.
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.
This press release contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this press release, are forward-looking statements. These statements relate to future events and involve known and unknown risks, including, without limitation, uncertainties regarding Strongbridge’s strategy, plans, outcomes of product development efforts, status and results of clinical trials, and objectives of management for future operations. The words “anticipate,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “project,” “target,” “will,” “would,” or the negative of these terms or other similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements are based on current expectations, estimates, forecasts and projections and are not guarantees of future performance or development and involve known and unknown risks, uncertainties and other factors. The forward-looking statements contained in this press release are made as of the date of this press release, and Strongbridge Biopharma does not assume any obligation to update any forward-looking statements except as required by applicable law.
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