Omecamtiv mecarbil is a first-in-class direct activator of cardiac myosin, the motor protein of the cardiac sarcomere that transfers chemical energy (ATP hydrolysis) into a mechanical force for contraction. By promoting the force generating cycle of myosin, the drug acts like “more hands on the rope” to improve cardiac contractility without increasing cardiac myocyte intracellular calcium concentrations. It is being evaluated as a potential treatment for heart failure with the goal of establishing a new continuum of care for patients in both in-hospital and outpatient settings. Part 1 will describe the discovery and selection of omecamtiv mecarbil, including the initial synthetic pathway and the development of an early stage manufacturing process to allow for rapid advancement in Phase 1/2A clinical evaluation. Part 2 will describe the design of a robust synthetic process to prepare omecamtiv mecarbil for pivotal clinical trials, and highlight the challenges and opportunities at the drug substance/drug product interface. This includes a convergent synthesis of the unsymmetrical urea core of the target from stable precursors, as well as engineering the drug substance particle properties to aid drug product performance. The discussion will also include key elements of the control strategy for genotoxic impurities and highlight the use of process analytical technology (PAT) tools to increase process knowledge and guide development.

Discovery and development of omecamtiv mecarbil - a novel cardiac myosin activator for the potential treatment of systolic heart failure

256th National Meeting (2018)

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