IS5MN PM
IS5MN PM is a novel formulation of Isosorbide-5-Mononitrate (IS5MN), an organic nitrate and the major biologically active metabolite of isosorbide dinitrate (ISDN), a vasodilator with effects on both arteries and veins. IS5MN is indicated for the treatment of angina pectoris, due to coronary artery disease. IS5MN PM has completed initial phase I clinical testing and has a comprehensive regulatory dossier available including a full US Investigational New Drug Application (IND). The regulatory approval strategy for this product is focused on a 505(b)(2) NDA which may help shorten the development and approval times for this product. IS5MN PM will provide significant incremental patient benefits via its novel formulation in the nitrate market through not only addressing issues of tolerance but also ensuring optimal drug exposure at the highest risk periods for patients.IS5MN is marketed at present in the US as immediate release or extended release tablets for the prevention of angina pectoris, due to coronary artery disease. The maximal effect of the extended release tablets occurs within 4 hours after dosing and persists for at least 12 hours. Since it is administered once daily in the morning, the maximum effect does not occur at the time of highest risk of cardiac events i.e., on awakening. In order to optimise the effect during waking hours and to minimise side effects and prevent the development of tolerance, a product that can be administered in the evening with onset beginning prior to waking the next morning would provide full coverage during waking hours, while allowing for a drug-free period during sleep to prevent the development of tolerance. In addition, such a mode of drug exposure should have a significant impact on the incidence of major cardiovascular events in the early morning period.
The IS5MN PM formulation has been designed to be administered in the evening just before bed with onset of action occurring prior to the patient wakening in the morning, not hours after waking. This allows the patient to be treated optimally during all waking hours of the day and, in particular, provides maximum exposure in the early morning high-risk period. In addition, following ingestion of IS5MN PM, drug release from the formulation tapers from 12 hours onwards after dosing, ensuring that tolerance to the drug does not develop. Therefore, the lowest concentrations following dosing with IS5MN PM coincide with the time of lowest risk of cardiovascular events i.e. evening and very early morning.