Lomitapide (DB08827): A Comprehensive Pharmacological and Clinical Monograph for the Management of Homozygous Familial Hypercholesterolemia

Introduction and Drug Profile

Overview and Therapeutic Context

Lomitapide is a first-in-class, orally administered small molecule inhibitor of the Microsomal Triglyceride Transfer Protein (MTP).[1] It represents a significant therapeutic innovation specifically developed as an adjunctive treatment for patients with Homozygous Familial Hypercholesterolemia (HoFH).[4] HoFH is a rare, life-threatening autosomal recessive or compound heterozygous genetic disorder of lipid metabolism characterized by a profound impairment or complete absence of low-density lipoprotein (LDL) receptor function.[6] This genetic defect leads to extremely elevated plasma concentrations of LDL-cholesterol (LDL-C) from birth, resulting in aggressive, premature atherosclerotic cardiovascular disease (ASCVD), often manifesting as major adverse cardiovascular events (MACE) in childhood, adolescence, or early adulthood.[7]

The defining therapeutic characteristic of Lomitapide is its novel mechanism of action, which is entirely independent of the LDL-receptor pathway.[9] Conventional lipid-lowering therapies, such as statins, primarily exert their effect by upregulating the expression of hepatic LDL receptors to enhance the clearance of circulating LDL particles. In HoFH patients, where these receptors are dysfunctional or absent, such therapies are often of limited efficacy.[6] Lomitapide circumvents this limitation by directly targeting the production of LDL precursors in the liver and intestine, thereby offering a potent LDL-C lowering effect in a patient population with a profound unmet medical need.