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.

Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.

BACKGROUND: Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain. METHODS: Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL, vs <15 mg/dL), before pooling estimates using multivariate random-effects meta-analysis. FINDINGS: Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change -39% [95% CI -43 to -35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs <15 mg/dL) were 1·04 (95% CI 0·91-1·18) for 15 mg/dL to less than 30 mg/dL, 1·11 (1·00-1·22) for 30 mg/dL to less than 50 mg/dL, and 1·31 (1·08-1·58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0·94 (0·81-1·10), 1·06 (0·94-1·21), and 1·43 (1·15-1·76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p=0·010) and was more pronounced at younger ages (interaction p=0·008) without effect-modification by any other patient-level or study-level characteristics. INTERPRETATION: In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials. FUNDING: Novartis Pharma AG.

Long-term safety of long-acting octreotide in patients with diabetic retinopathy: results of pooled data from 2 randomized, double-blind, placebo-controlled phase 3 studies.

PURPOSE: Octreotide (OCT) has been successfully used for treatment of acromegaly and neuroendocrine tumors for more than 30 years. However, long-term safety of OCT has not been documented in placebo-controlled setting. This present analysis pooled safety data from two similarly-designed, randomized, and placebo-controlled studies to evaluate long-term safety of long-acting OCT (20, 30 mg); targeted post-hoc analyzes focused on cardiac, hepatic, and renal safety. METHODS: Two studies (NCT00131144, NCT001308450) were conducted in patients with diabetic retinopathy (OCT20 = 191, OCT30 = 348, placebo = 347). In this analysis, patients were stratified based on baseline glomerular filtration rate. Hepatic, cardiac, and renal adverse events (AEs) were identified by standardized MedDRA queries. RESULTS: Median duration of exposure was >3.5 years. Most common AEs reported with OCT were diarrhea, cholelithiasis, hypoglycemia, nasopharyngitis, and hypertension. Incidence of cardiac events (QT prolongation and arrhythmia) with OCT20 and OCT30 were comparable to placebo (OCT20, RR = 1.11 [95% CI, 0.61-2.03]; OCT30, RR = 1.09 [95% CI, 0.70-1.68]). For ECG findings, changes in QTcF were similar in treatment groups, and outliers did not exceed 480 ms. Incidence of cardiac ischemia was lower with OCT than placebo (OCT20 = 12.6%, OCT30 = 10.6%, placebo = 15.3%). Incidence of liver-related AEs was higher with OCT30 than placebo (RR = 2.04 [95% CI, 1.28-3.26]); incidences were comparable with OCT20 and placebo (RR = 1.50 [95% CI, 0.69-3.25]). Overall incidences of renal AEs were comparable between treatment groups (OCT20 = 5.8%; OCT30 = 6.3%; placebo = 7.2%). Drug-related SAEs were reported more frequently with OCT (OCT20 = 7.9%; OCT30 = 10.1%; placebo = 3.5%); predominantly gallbladder-related, GI-related, and hypoglycemia. CONCLUSIONS: The results from these long-term placebo-controlled studies confirm the established safety profile of long-acting OCT, in particular low risk of cardiac, hepatic and renal toxicity in a high-risk population.