Dose Selection for a Direct and Selective Factor IXa Inhibitor and its Complementary Reversal Agent: Translating Pharmacokinetic and Pharmacodynamic Properties of the REG1 System to Clinical Trial Design
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We performed detailed pharmacokinetic and pharmacodynamic modeling of REG1, an anticoagulation system composed of the direct factor IXa (FIXa) inhibitor pegnivacogin (RB006) and its matched active control agent anivamersen (RB007), with a focus on level of target inhibition to translate phase 1 results to phase 2 dose selection. We modeled early-phase clinical data relating weight-adjusted pegnivacogin dose and plasma concentration to prolongation of the activated partial thromboplastin time (aPTT). Using an in vitro calibration curve, percent FIXa inhibition was determined and related to aPTT prolongation and pegnivacogin dose and concentration. Similar methods were applied to relate anivamersen dose and level of reversal of pegnivacogin anticoagulation. Combined early-phase data suggested that ≥0.75 mg/kg pegnivacogin was associated with >99% inhibition of FIX activity and prolongation of plasma aPTT values ≈2.5 times above baseline, leading to selection of a 1 mg/kg dose for a phase 2a elective percutaneous coronary intervention study to achieve a high intensity of anticoagulation and minimize intersubject variability. Phase 2 validated our predictions, demonstrating 1 mg/kg pegnivacogin yielded plasma concentrations ≈25 μg/ml and >99% inhibition of FIX activity. The relationship between the anivamersen to pegnivacogin dose ratio and degree of pegnivacogin reversal was also validated. Our approach decreased the need for extensive dose–response studies, reducing the duration, complexity and cost of clinical development. The 1 mg/kg pegnivacogin dose and a range of anivamersen dose ratios are being tested in the phase 2b RADAR study (NCT00932100).
KeywordsPegnivacogin Anivamersen Factor IXa inhibition Dose selection
We would like to thank the CLIN101, 102, 103, and 210 clinical site investigators and research team personnel who diligently executed the study protocols, provided important feedback for future study design, and produced high quality data to support the continued development of the REG1 System. We also thank Elizabeth Cook for exceptional editorial input and assistance.
Dr. Rusconi is a founder, employee, and stockholder in REGADO Biosciences. Dr. Zelenkofske is an employee and stockholder in REGADO Biosciences. Dr. Wargin is a consultant for REGADO Biosciences. Drs. Becker, Povsic, Harrington, and Alexander are employed by the Duke Clinical Research Institute which has received research funding from REGADO Biosciences.
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