[Pharmacological and clinical profile of inclisiran sodium, a long-acting LDL cholesterol lowering siRNA, LEQVIO for s.c. injection syringe 300†|mg].

Inclisiran sodium (Brand name: LEQVIO® for s.c. injection syringe 300 |mg, hereinafter referred to as inclisiran), a small interfering ribonucleic acid (siRNA) product that targets the mRNA that encodes the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein was approved on September 25, 2023 for the indication of "Familial hypercholesterolemia, hypercholesterolemia" in Japan. Inclisiran is conjugated on the sense strand with triantennary N-acetylgalactosamine to facilitate uptake by hepatocytes. In vitro and in vivo pharmacology studies demonstrated the lowering effects of PCSK9 and LDL-C in hepatocytes and cynomolgus monkeys. It was considered unlikely to cause clinically significant risks due to toxicities arising from complementary binding to non-target RNA sequences (hybridization-dependent off-target effects). Clinical trials conducted globally including Japan in patients with familial hypercholesterolemia and hypercholesterolemia who did not reach the LDL-C target showed that inclisiran sodium 300 |mg dosed at Day 1, Day 90 and then every 6 months demonstrated significant LDL-C reduction and the efficacy sustained long. The majority of patients achieved the guideline recommended LDL-C targets. Inclisiran sodium 300 |mg was well tolerated and there were no specific safety concerns. Therefore, inclisiran is expected to be a new therapeutic option for the patients with familial hypercholesterolemia and hypercholesterolemia.

Efficacy, Safety, and Pharmacokinetics of Inclisiran in Japanese Patients: Results from ORION-15.

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.

Pharmacokinetics After Single Ascending Dose, Food Effect, and Safety of Sacubitril/Valsartan (LCZ696), an Angiotensin Receptor and Neprilysin Inhibitor, in Healthy Japanese Subjects.

BACKGROUND AND OBJECTIVES: LCZ696 (sacubitril/valsartan) is a novel angiotensin receptor neprilysin inhibitor (ARNI) that has been developed for treatment of heart failure patients with reduced ejection fraction and approved in the US, Europe, and many other countries. METHODS: This randomized, placebo-controlled study was conducted in healthy Japanese male subjects (N = 50) to assess the pharmacokinetics and safety of single ascending oral doses (20-600 mg) of LCZ696. Food effect was also evaluated following administration of 200 mg dose. Plasma and urine samples from 40 subjects receiving LCZ696 were collected to assess pharmacokinetics of LCZ696 analytes (sacubitril, sacubitrilat, and valsartan). RESULTS: Following single oral dose administration of LCZ696, sacubitril and valsartan rapidly appeared in systemic circulation with a dose-linear increase in the exposure to the LCZ696 analytes. Of the administered dose, approximately 0.85 %, 54.0 %, and 8.19 % of sacubitril, sacubitrilat, and valsartan, respectively, were recovered in urine. Food reduced AUC of sacubitril, sacubitrilat, and valsartan by 21, 8, and 40 %, respectively, and C max by 72, 27, and 51 %, respectively. CONCLUSION: Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects.

Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects.

LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 µg single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions.

Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction.

This 8-week, multi-center, open-label study assessed the safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Patients (n=32) with mean sitting systolic blood pressure (msSBP) ⩾140 mm Hg (after a 2-5-week washout of previous antihypertensive medications) and estimated glomerular filtration rate (eGFR) ⩾15 and <60 ml min(-1) 1.73 m(-2) received LCZ696 100 mg with an optional titration to 200 and 400 mg in a sequential manner starting from Week 2 in patients with inadequate BP control (msSBP ⩾130 mm Hg and mean sitting diastolic blood pressure (msDBP) ⩾80 mm Hg) and without safety concerns. Safety was assessed by monitoring and recording all adverse events (AEs) and change in potassium and creatinine. Efficacy was assessed as change from baseline in msSBP/msDBP. The mean baseline BP was 151.6/86.9 mm Hg, urinary albumin/creatinine ratio (UACR) geometric mean was 7.3 mg mmol(-1) and eGFR was ⩾30 and <60 in 25 (78.1%) patients and was ⩾15 and <30 in 7 (21.9%) patients. Fourteen (43.8%) patients reported at least one AE, which were mild in severity. No severe AEs or deaths were reported. There were no clinically meaningful changes in creatinine, potassium, blood urea nitrogen and eGFR. The geometric mean reduction in UACR was 15.1%, and the mean reduction in msSBP and msDBP was 20.5±11.3 and 8.3±6.3 mm Hg, respectively, from baseline to Week 8 end point. LCZ696 was generally safe and well tolerated and showed effective BP reduction in Japanese patients with hypertension and renal dysfunction without a decline in renal function.

No regional differences of cytochrome P450 expression in the liver of Cynomolgus monkeys (Macaca fascicularis).

Non-human primates are frequently used in toxicological studies the result of which are extrapolated to humans, but background data on drug metabolism ability among monkeys derived from different countries has not been published, especially on the key enzyme, cytochrome P450 (CYP450). We assessed the amounts of hepatic CYP450 obtained from cynomolgus monkeys of different ages and from different countries in this study. There were no regional differences of total P450 content, as well as major CYP450 isozymes (CYP 1A, 2A, 2B, 2C, 2D, 2E1 and 3A4) in cynomolgus monkeys by westernblot analysis. Similarly, there were no significant differences with hybrid cynomolgus monkeys, but variations in individual values were large. As for aging, total P450 contents declined in old cynomolgus monkeys (12-32 years of age). These results indicate the usefulness of basic data of hepatic CYP450 obtained from cynomolgus monkeys of different ages and from different countries.

The effects of diabetes with hyperlipidemia on P450 expression in APA hamster livers.

The effect of chronic hyperglycemia and hyperlipidemia induced by streptozotocin (SZ) on the expression of P450 in the liver of APA hamsters was studied in this experiment. No effect on the total activity of P450 was seen in SZ-induced diabetic hamsters throughout the experimental period. At 1 and 6 months after SZ-injection, the levels of CYP1A, 2C6, and 3A of SZ-injected hamsters were much lower than those of age-matched control hamsters. CYP2B expression tended to decrease and CYP2E1 and 4A expression tended to increase in SZ-injected hamsters, although the results were not significant. At 3 months after SZ-injection, however, no significant difference between SZ-injected and normal hamsters was seen in these P450 isozymes. On the other hand, CYP2C11 expression was slightly depressed in SZ1M and SZ6M, and almost equivalent to control hamsters in SZ3M. Immunohistochemistry by the use of each isozyme antibody revealed that SZ-induced diabetes affected the localization of CYP2C6, 3A, and 4A in the hepatic acinus. The expression of CYP2C6 and 3A was depressed mainly in the periportal region of the acinus, and CYP4A expression was induced mainly in the perivenous region by SZ-induced diabetes. On the other hand, the expression pattern of CYP1A, 2B, 2C11, and 2E1 were not affected. These results demonstrate that the effects of SZ-induced diabetes on hepatic P450 differ for each isozyme in APA hamsters and also differ from those of other experimental diabetic animals, including golden hamsters.