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Aim: To evaluate the efficacy, safety, and pharmacokinetics (PK) of inclisiran in Japanese patients with high cardiovascular risk and elevated low-density lipoprotein cholesterol (LDL-C)., Methods: ORION-15 was a phase 2, double-blind, placebo-controlled randomized trial. Patients with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH), were randomized to inclisiran sodium 100, 200, or 300 mg, or placebo and dosed subcutaneously on Days 1, 90, and 270. The primary endpoint was the percentage change from baseline to Day 180 to demonstrate the superiority of inclisiran vs. placebo. Patients who consented to the PK substudy had additional study procedures for blood collection and safety assessment., Results: Overall, 312 patients (mean age, 63.6 years; male, 74.4%; baseline LDL-C, 114.0 mg/dL) were randomized. Baseline characteristics were well balanced among the groups. At Day 180, inclisiran at all doses demonstrated significant LDL-C and proprotein convertase subtilisin/kexin type 9 (PCSK9) reductions (p＜0.0001 for both), which showed a dose-response relationship. The greatest reductions (LDL-C, 65.3%; PCSK9, 79.2%) were with inclisiran sodium 300 mg. At Day 180, ＞86% of the patients receiving inclisiran achieved the Japan Atherosclerosis Society 2017 lipid management targets compared to 8.9% for placebo. The mean (SD) plasma half-life for inclisiran was 6.8 (2.0)-7.6 (0.8) h. The incidence of adverse events with inclisiran was similar to that with placebo., Conclusion: Inclisiran sodium 100, 200, and 300 mg demonstrated clinically meaningful and statistically significant LDL-C and PCSK9 reductions at Day 180, which were consistent over 12 months. Inclisiran was effective and well tolerated in Japanese patients with hypercholesterolemia, including HeFH.

• In the 1970 s, Akira Endo succeeded in extracting statin (compactin) from mold. • In Japan, LDL-R mutations were the most frequent, followed by PCSK9 gain-of-function mutation. • In Chiba, next-generation sequencing in outpatients with FH identified mutations in LDL-R, PCSK9, or ABCG5/8. • The K811X mutation in LDL-R is the most common in Kanazawa, but not detected at all in Chiba. Familial hypercholesterolemia (FH) is an inherited disorder characterized by increased low-density lipoprotein LDL) cholesterol and atherosclerotic cardiovascular disease. Although initial genetic analysis linked FH to LDL receptor mutations, subsequent work demonstrated that a gain-of-function mutation in the proprotein convertase subtilisin/kexin type 9 (PCSK9), which causes LDL-R degradation, was shown to be the cause of FH. In this review, we describe the history of research on FH, its clinical phenotyping and genotyping and advances in treatment with special focus on Japan. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to elucidate the gene and lipid profiles of children clinically diagnosed with familial hypercholesterolemia (FH)., Methods: A total of 21 dyslipidemia-related Mendelian genes, including FH causative genes (LDLR, APOB, and PCSK9) and LDL-altering genes (APOE, LDLRAP1, and ABCG5/8), were sequenced in 33 Japanese children (mean age, 9.7±4.2 years) with FH from 29 families., Results: Fifteen children (45.5%) with pathogenic variants in LDLR (eight different heterozygous variants) and one child (3.0%) with the PCSK9 variant were found. Among 17 patients without FH causative gene variants, 3 children had variants in LDL-altering genes, an APOE variant and two ABCG8 variants. The mean serum total cholesterol (280 vs 246 mg/dL), LDL-cholesterol (LDL-C, 217 vs 177 mg/dL), and non-HDL cholesterol (228 vs 188 mg/dL) levels were significantly higher in the pathogenic variant-positive group than in the variant-negative group. In the variant-positive group, 81.3% of patients had LDL-C levels ≥ 180 mg/dL but 35.3% in the variant-negative group. The mean LDL-C level was significantly lower in children with missense variants, especially with the p.Leu568Val variant, than in children with other variants in LDLR, whereas the LDL-altering variants had similar effects on the increase in serum LDL-C to LDLR p.Leu568Val., Conclusion: Approximately half of the children clinically diagnosed with FH had pathogenic variants in FH causative genes. The serum LDL-C levels tend to be high in FH children with pathogenic variations, and the levels are by the types of variants. Genetic analysis is useful; however, further study on FH without any variants is required.

Background and Aims: Genetic identification is a public health care concern for management of familial hypercholesterolemia (FH) associated cardiovascular morbidity and mortality. This study presents the spectrum and distribution of LDLR, APOB, PCSK9 gene mutations in Asia., Methods: Databases were searched for English papers from 1950 to 2019. The spectrum of the variants was investigated in 8994 FH families in 48 Asian countries. We determined the frequency of variants, zygosity, and clinical features., Results: Twenty countries have studied LDLR variants. A total of 629 mutations were reported and twenty variants were accounted as common variants in different populations. China, Japan, India and Taiwan constituted 68% of published articles. The most frequent mutation was reported in Japan but was not common in other countries. Other missense variants accounted for 50% of the mutations, frameshifts 19%, and nonsense 11%. The pooled frequency of variation was estimated in 1867 individuals. Approximately 67% of Iranian families were homozygous.,The common variant was p.Ser130Ter. p.Arg3527Trp in APOB was common among 184 heterozygous patients; the common variant of PCSK9 was p.Glu32Lys., Conclusions: This is the first systematic review of LDLR, APOB, PCSK9 mutations in FH patients in Asia. These findings underscore the need to fill in the gap of studies on different populations in Asia. It also underlies the importance of early detection and management to decrease atherosclerosis and cardiovascular risk in different ethnicities., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: More than 4970 variants in the low-density lipoprotein receptor (LDLR) gene and 350 variants in the proprotein convertase subtilisin/kexin 9 (PCSK9) gene have been reported in familial hypercholesterolemia (FH) patients. However, the effects of these variants on FH pathophysiology have not been fully clarified. We aimed to update the LDLR and PCSK9 variants in Japanese heterozygous FH (HeFH) patients and annotate their clinical significance for the genetic diagnosis of HeFH., Methods: A genetic analysis of the LDLR and PCSK9 genes was performed in 801 clinically diagnosed HeFH patients. The association of the pathogenic variants with the clinical FH phenotype was examined., Results: Pathogenic variants in the LDLR and PCSK9 genes were found in 46% (n = 296) and 7.8% (n = 51) of unrelated FH patients (n = 650), respectively. The prevalence of Achilles tendon thickness was low (44%) in patients harbouring PCSK9 pathogenic variants. Furthermore, 17% of unrelated FH patients harboured one of five frequent LDLR pathogenic variants: c.1845+2T > C, c.1012T > A: p.(Cys338Ser), c.1297G > C: p.(Asp433His), c.1702C > G: p.(Leu568Val), and c.2431A > T: p.(Lys811*). Patients harbouring the c.1845+2T > C and c.1702C > G: p.(Leu568Val) variants had significantly lower serum LDL-cholesterol levels and higher serum HDL-cholesterol levels, respectively, compared with those harbouring the other LDLR pathogenic variants. The proportion of LDLR pathogenic variants was higher in patients with a younger age of coronary artery disease (CAD) onset and significantly decreased as the age of CAD onset increased., Conclusions: This study annotated the clinical significance and characteristics of LDLR and PCSK9 pathogenic variants in Japanese HeFH patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The addition of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to statin therapy reduces the rate of cardiovascular events. This study examined the cost-effectiveness of PCSK9 inhibitor+statin compared with standard therapy (statin monotherapy) in the treatment of triple-vessel coronary artery disease (CAD) in Japan. Methods and Results: A Markov model was applied to assess the costs and benefits associated with PCSK9 inhibitor+statin over a projected 30-year period from the perspective of a public healthcare payer in Japan. The incremental cost-effectiveness ratio (ICER), expressed as the quality-adjusted life-years (QALYs), was estimated. The effects on survival and numbers of events were based on the FOURIER trial and the CREDO Kyoto registry. The ICER of PCSK9 inhibitor+statin over standard therapy was 13.5 million (95% confidence interval 7.6-23.5 million) Japanese Yen (JPY) per QALY gained for triple-vessel CAD. The probability of the cost-effectiveness of PCSK9 inhibitor+statin vs. standard therapy was 0.0008% at a cost-effectiveness threshold of 5 million JPY. In patients with poorly controlled familial hypercholesterolemia (FH) with triple-vessel CAD, the ICER was 3.4 million JPY per QALY gained., Conclusions: PCSK9 inhibitor plus statin did not show good cost-effectiveness for triple-vessel CAD; however, it showed good cost-effectiveness for patients with triple-vessel CAD and poorly controlled FH in Japan.

Backgrounds: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by hypercholesterolemia, tendon xanthomas, and premature coronary heart disease. FH is caused by mutations of "FH genes," which include the LDL-receptor (LDLR), apolipoprotein B-100 (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9). We evaluated the usefulness of FH gene analysis for diagnosing homozygous FH (homo-FH), particularly in cases caused by gain-of-function (g-o-f) mutations in PCSK9 (PCSK9 E32K)., Objectives: To evaluate the frequency of homo-FH caused by PCSK9 E32K compared with FH due to other genetic causes and to report the phenotypic features of homo-FH caused by PCSK9 E32K., Methods: Genomic DNA was prepared from white blood cells, and LDLR and PCSK9 mutations were identified using the Invader assay method., Results: Of the 1055 hetero-FH patients, 62 patients (5.9%) carried the PCSK9 E32K mutation, while in the 82 alleles of 41 homo-FH patients, 13 (15.9%) had double mutations of LDLR allele and PCSK9 E32K mutation. Mean plasma total cholesterol (TC) (9.93 ± 2.95 mmol/L, mean ± SD) in true homo-FH cases with PCSK9 E32K or double hetero-FH cases with PCSK9 E32K and LDLR mutations were significantly lower than those in true homo-FH (18.06 ± 4.96 mmol/L) and compound heterozygous cases with LDLR mutations (14.84 ± 1.62 mmol/L). Mean plasma TC concentrations in the 59 hetero-FH cases with PCSK9 E32K (7.21 ± 1.55 mmol/L) were significantly lower than those (8.94 ± 1.53 mmol/L) in the hetero-FH by LDLR mutations., Conclusions: FH caused by PCSK9 g-o-f mutations is relatively common in Japan and causes a mild type of homo- and hetero-FH compared with FH caused by LDLR mutations., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)