Eniluracil (DB03516): A Comprehensive Monograph on a Dihydropyrimidine Dehydrogenase Inactivator—From Clinical Failure to Renewed Therapeutic Promise

Executive Summary

Eniluracil is a small molecule, uracil analogue developed as a potent, mechanism-based, and irreversible inhibitor of the enzyme dihydropyrimidine dehydrogenase (DPD).[1] Its sole therapeutic purpose is to be co-administered with fluoropyrimidine chemotherapies, most notably 5-fluorouracil (5-FU), to fundamentally alter their pharmacokinetics and enhance their therapeutic index.[3] DPD is the rate-limiting enzyme responsible for the rapid catabolism of over 80% of an administered 5-FU dose, which results in a short plasma half-life and erratic oral bioavailability.[3] Eniluracil's complete and prolonged inactivation of DPD promised to transform 5-FU into a reliable, orally administered agent with predictable, linear pharmacology, effectively mimicking the therapeutic exposure of a continuous intravenous infusion.[3]

The initial clinical development of Eniluracil showed considerable promise, with Phase I and II studies confirming its profound pharmacological effects and demonstrating antitumor activity in various solid malignancies.[7] However, this trajectory was abruptly halted by the failure of two large-scale, pivotal Phase III trials in metastatic colorectal cancer. In these studies, the oral Eniluracil/5-FU combination regimen proved to be statistically inferior to the standard-of-care intravenous 5-FU/leucovorin, failing to meet its primary endpoint of equivalent overall survival and showing a shorter progression-free survival.[9]