A First-in-Class Drug, Lomitapide, Tailored to Patients with Homozygous Familial Hypercholesterolemia is Just about Meeting with Good News to Them

A raised low-density lipoprotein (LDL) cholesterol (LDL-C) is one of the major risk factors for ath-erosclerotic cardiovascular disease (ASCVD) 1-3). Homozygous family hypercholesterolemia (HoFH) is a rare inherited disease characterized by markedly elevated levels of LDL-C, generally more than 500 mg/ dL when untreated, and a high risk of premature ASCVD 4). HoFH is caused by loss-of-function mutations in the LDL receptor-related genes, including LDLR true homozygotes, two LDLR compound het-erozygotes, and gene mutations accompanied with gain-of-function of proprotein convertase subtilisin/ kixin type 9 (PCSK9) 4-7). In any case, LDL receptors of HoFH patients are absent or defective. Statins are a main first-line drug for LDL-lowering therapy with certainty, but the recent developments in LDL-lowering drugs have been remarkable 8). This lineup is composed of the cholesterol absorption inhibitor ezetimibe, monoclonal antibodies against PCSK9, and inhibitors of apolipoprotein B-containing lipoprotein production. European Atherosclerosis Society and American Heart Association similarly have defined the LDL-C target for HoFH adults as less than 100 mg/dL or 70 mg/dL in the presence of ASCVD 1, 9). The Japan Atherosclerosis Society recommends the primary LDL-C target as less than 100 mg/ dL and the secondary target as less than 50% reduction from pretreatment LDL-C levels 10). Statins and PCSK9 inhibitors would be effective in a limited manner for LDL-lowering and ASCVD prevention in HoFH with the absent or defective LDL receptors because these drugs decrease LDL-C levels by up-regulating LDL receptors although it has reported that LDL-lowering therapy mainly with statins is associated with delayed cardiovascular events and prolonged survival in HoFH patients 11). Nowadays, lomitapide is approved as a first-in-class drug for lowering LDL-C levels in HoFH adults in western countries and Japan, and it is a selective inhibitor of microsomal triglyceride transfer protein (MTP) that transfers triglycerides onto newly synthesized apolipoprotein B leading to the formation of very-low-density lipoprotein (VLDL) in the liver 8, 12). Loss of function mutations in both alleles of MTTP results in abetalipoproteinemia, which is characterized by the absence of apolipoprotein B, VLDL, and LDL in the plasma due to failure of the liver to produce VLDL. Lomitapide therapy inhibits MTP activity and reduces the production and secretion of chylomicrons by the intestine and VLDL by the liver leading to reductions in LDL-C, apolipoprotein B, triglyceride, non–high-density lipoprotein (HDL) cholesterol, and lipoprotein (a) [Lp(a)]. Namely, lomitapide is expected to lower LDL-C through LDL receptor independent mechanisms. The present study …