Lapaquistat (TAK-475): A Comprehensive Pharmacological and Clinical Retrospective of a Squalene Synthase Inhibitor

Executive Summary

Lapaquistat, developed by Takeda Pharmaceutical Company under the code TAK-475, represents a significant chapter in the history of lipid-lowering drug development. It emerged as a first-in-class squalene synthase inhibitor, a novel therapeutic strategy conceived to circumvent the known limitations of statins, particularly statin-associated muscle symptoms. The core of its design was a downstream inhibition of the cholesterol biosynthesis pathway, a mechanistically elegant approach intended to reduce cholesterol production without depleting essential non-sterol isoprenoids. Extensive Phase 2 and 3 clinical trials, involving over 6,000 patients, confirmed that Lapaquistat effectively lowered low-density lipoprotein cholesterol (LDL-C) and other atherogenic markers in a dose-dependent manner. However, this efficacy was overshadowed by a critical safety signal. At the most effective therapeutic dose of 100 mg, Lapaquistat was associated with a significant incidence of elevated liver transaminases, culminating in two cases that met the criteria for Hy's Law—a strong predictor of severe drug-induced liver injury. This dose-limiting hepatotoxicity, coupled with the insufficient efficacy of the safer 50 mg dose, rendered the drug commercially non-viable, leading to the termination of its development program in 2008. Despite this clinical failure, the story of Lapaquistat did not end. Post-hoc research has unveiled remarkable potential for its repurposing. Its precise on-target mechanism is now being explored as a novel host-directed therapy for the parasitic disease cryptosporidiosis and as a potential treatment for the rare genetic inflammatory disorder, Mevalonate Kinase Deficiency. Lapaquistat thus serves as a compelling case study in rational drug design, the unforeseen complexities of metabolic intervention, and