LAUSR

Address for correspondence: Mariko Harada-Shiba, Cardiovascular Center, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686 E-mail: [email protected] Received: May 6, 2022 Accepted for publication: May 7, 2022 Pa t i e n t s w i t h h o m o z y g o u s f a m i l i a l hypercholesterolemia (HoFH) exhibit a severe phenotype, including extremely elevated low-density lipoprotein cholesterol (LDL-C), cutaneous and/or tendon xanthomas, and premature atherosclerosis1). Atherosclerosis in patients with HoFH includes coronary artery disease, aortic valve, and supra-aortic valve stenosis, which sometimes can lead to death. HoFH is caused by biallelic pathogenic mutations in genes related to LDL receptor metabolism, such as LDL receptor (LDLR), proprotein convertase subtilisin/kexin 9 (PCSK9), apolipoprotein B (APOB), and LDLR adaptor protein 1 (LDLRAP1)2). Atherosclerotic cardiovascular events were reported to occur when the amount of LDL-C accumulation reaches the threshold3). LDL-C levels in patients with HoFH are extremely high from birth, resulting in reaching the threshold in childhood or adolescence. To prevent atherosclerotic cardiovascular diseases in HoFH, strict control of LDL-C levels is strongly recommended4). Most lipid lowering drugs, including statins, have a limited effect in patients with HoFH, who lack LDL receptor activity. Lipoprotein apheresis has been the main strategy for treating HoFH5). Lomitapide is a drug targeting microsome triglyceride transfer protein, which plays a key role in the synthesis of very-low density lipoprotein (VLDL) in the liver and chylomicron in the intestine6). Developed as a lipid lowering drug7), lopmitapide was shown to cause adverse events, including diarrhea and lipid deposition in the liver, which resulted in discontinuing development. Recently, lomitapide has been shown to reduce LDL-C levels in patients with HoFH independent of their genotypes and approved in many countries, including Japan8, 9). In the phase 3 study in Japan, nine patients with HoFH were enrolled with lomitapide added to lipid lowering therapies, including lipoprotein apheresis8). The study was conducted in three phases— pretreatment run-in period (weeks −6 to 0), dose escalation, and efficacy period (0–26 weeks) and safety period (26–56 weeks). During the dose escalation and efficacy period, lomitapide was initiated at 5 mg/day and increased to each patient’s maximum tolerated dose (MTD) (maximum: 60 mg/day). The MTDs were 5 mg/day in two, 10 mg/day in one, 20 mg/day in five, and 40 mg in one patient. The average MTD was 17.8 mg/day. The LDL-C decrease at the primary endpoint (26 weeks) was 38%. In the phase 3 study conducted in USA, Canada, South Africa, and Italy, the average MTD was 43.7 mg/day and LDL-C decrease was 50% at week 26 9). Thus, the MTD in Japanese was less than half that in Caucasians. In the clinical setting, we tried to prescribe the drug according to the phase 3 study. We would like to present the case of a patient with HoFH, who received lomitapide and experienced typical adverse events.