From network analysis to experimental validation: identification of regulators of non-muscle myosin II contractility using the folded-gastrulation signaling pathway.

The morphogenetic process of apical constriction, which relies on non-muscle myosin II (NMII) generated constriction of apical domains of epithelial cells, is key to the development of complex cellular patterns. Apical constriction occurs in almost all multicellular organisms, but one of the most well-characterized systems is the Folded-gastrulation (Fog)-induced apical constriction that occurs in Drosophila. The binding of Fog to its cognizant receptors Mist/Smog results in a signaling cascade that leads to the activation of NMII-generated contractility.

The N-Acetylgalactosamine-conjugated small interfering RNA inclisiran can be coadministered safely with atorvastatin in cynomolgus monkeys resulting in additive low-density lipoprotein cholesterol reductions.

Inclisiran, a small interfering RNA, selectively inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis in the liver and has been shown to reduce low-density lipoprotein cholesterol (LDL-C) by ≥50% in patients with hypercholesterolemia receiving maximally tolerated statins. The toxicokinetic, pharmacodynamic, and safety profiles of inclisiran when coadministered with a statin were characterized in cynomolgus monkeys. Six cohorts of monkeys were administered either atorvastatin (40 mg/kg, reduced to 25 mg/kg during the study, daily, oral gavage), inclisiran (300 mg/kg every 28 days, subcutaneous administration), atorvastatin (40/25 mg/kg) and inclisiran combinations (30, 100, or 300 mg/kg), or control vehicles over 85 days followed by 90 days' recovery.

An evaluation of a supratherapeutic dose of inclisiran on cardiac repolarization in healthy volunteers: A phase I, randomized study.

Inclisiran is a small interfering RNA molecule that has been shown to provide an effective and sustained reduction in low-density lipoprotein cholesterol levels. This study aimed to determine whether a supratherapeutic dose of inclisiran affects cardiac repolarization and conduction in healthy volunteers. A phase I, randomized, double-blind, double-dummy, placebo- and positive-controlled, three-way crossover study was performed in 48 healthy volunteers.

Evaluation of the distribution and excretion of [C]-inclisiran following single subcutaneous administration in cynomolgus monkeys.

Inclisiran is a small interfering RNA molecule that was designed to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels by inhibiting proprotein convertase subtilisin/kexin type 9 synthesis in the liver. This study aimed to characterize the tissue distribution and excretion of inclisiran after dosing in monkeys. A single 20 mg/kg subcutaneous injection of [C]-inclisiran was administered to 12 male cynomolgus monkeys.

Pharmacokinetics and pharmacodynamics of inclisiran, a small interfering RNA therapy, in patients with hepatic impairment.

Background: Inclisiran, a small interfering RNA molecule, reduces low-density lipoprotein cholesterol (LDL-C) by inhibiting production of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the liver.

Objective: To investigate the pharmacokinetics, pharmacodynamics, and safety of inclisiran in patients with mild or moderate hepatic impairment (HI) vs participants with normal hepatic function (NHF).

Methods: In this single-center, open-label, parallel-group study, patients with mild (Child-Pugh A) or moderate (Child-Pugh B) HI and with NHF, matched by age, body mass index, sex, and race (if possible), received a single subcutaneous therapeutic dose of inclisiran (300 mg).

Incidence, predictors, and outcomes associated with acute kidney injury in patients undergoing transcatheter aortic valve replacement: from the BRAVO-3 randomized trial.

Background: Acute kidney injury (AKI) is not uncommon in patients undergoing transcatheter aortic valve replacement (TAVR).

Objective: We examined the incidence, predictors, and outcomes of AKI from the BRAVO 3 randomized trial.

Methods: The BRAVO-3 trial included 802 patients undergoing transfemoral TAVR randomized to bivalirudin vs.

Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis.

Background: Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin-kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing.

Objectives: The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran.

Methods: Participants with heterozygous familial hypercholesterolemia (ORION-9 [Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)]), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]), or ASCVD and ASCVD risk equivalents (ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]) taking maximally tolerated statin therapy, with or without other LDL-C-lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days.

Effect of inclisiran, the small-interfering RNA against proprotein convertase subtilisin/kexin type 9, on platelets, immune cells, and immunological biomarkers: a pre-specified analysis from ORION-1.

Aims: Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported.

Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia.

Background: Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia.

Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol.

Background: Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing.

Methods: We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose.

Effects of Renal Impairment on the Pharmacokinetics, Efficacy, and Safety of Inclisiran: An Analysis of the ORION-7 and ORION-1 Studies.

Objective: To investigate the pharmacodynamic properties of inclisiran, a small interfering RNA targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), in individuals with normal renal function and renal impairment (RI).

Patients And Methods: The analysis included participants with normal renal function and mild, moderate, and severe RI from the phase 1 ORION-7 renal study (n=31) and the phase 2 ORION-1 study (n=247) who received 300 mg of inclisiran sodium or placebo.

Results: In ORION-7, PCSK9 values were reduced at day 60 in the normal renal function group (68.

Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial.

Importance: Sustained reductions in low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies that require frequent dosing are reliant on patient adherence, and poor adherence is associated with worse clinical outcomes.

Objective: To determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen.

Design, Setting, And Participants: Prespecified analysis of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial.

Impact of percutaneous closure device type on vascular and bleeding complications after TAVR: A post hoc analysis from the BRAVO-3 randomized trial.

Background/objective: Prostar XL (PS) and ProGlide (PG) are common vascular closure devices (VCD) used in TAVR via transfemoral vascular approach. The impact of these VCD on vascular and bleeding complications remains unclear.

Methods: The BRAVO-3 trial randomized 802 patients undergoing transfemoral TAVR.

Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial.

Objective: To evaluate the efficacy and safety of inclisiran by diabetes status.

Research Design And Methods: ORION-1 (ClinicalTrials.gov, NCT02597127) randomized 501 subjects with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents and high LDL cholesterol (LDL-C), despite maximally tolerated LDL-C-lowering therapies, to one or two doses of placebo or inclisiran.

Inclisiran for the treatment of cardiovascular disease: the ORION clinical development program.

Inclisiran is a novel drug that inhibits PCSK9 synthesis specifically in the liver, harnessing the natural mechanism of RNAi. Phase I and II data show that inclisiran lowers low-density lipoprotein cholesterol levels on average by >50% with a duration of effect that enables twice-yearly dosing. Phases I, II and emerging Phase III data support inclisiran's safety, tolerability and risk-benefit profile.

Effect of Infusion of High-Density Lipoprotein Mimetic Containing Recombinant Apolipoprotein A-I Milano on Coronary Disease in Patients With an Acute Coronary Syndrome in the MILANO-PILOT Trial: A Randomized Clinical Trial.

Importance: Infusing a high-density lipoprotein mimetic containing apolipoprotein A-I Milano demonstrated potential atheroma regression in patients following an acute coronary syndrome. To our knowledge, the effect of infusing a new mimetic preparation (MDCO-216) with contemporary statin therapy is unknown.

Objective: To determine the effect of infusing MDCO-216 on coronary atherosclerosis progression.

Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins: Prespecified Secondary End Points in ORION 1.

Background: The ORION-1 trial (Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol [LDL-C]) demonstrated that inclisiran, an siRNA therapeutic that targets protease proprotein convertase subtilisin/kexin type 9 mRNA within hepatocytes, produces significant low-density lipoprotein cholesterol reduction. The effects of inclisiran on other lipids are less well described.

Methods: ORION-1 was a phase 2 trial assessing 6 different inclisiran dosing regimens versus placebo.

MDCO-216 Does Not Induce Adverse Immunostimulation, in Contrast to Its Predecessor ETC-216.

Purpose: Aim of this study was to demonstrate that MDCO-216 (human recombinant Apolipoprotein A-I Milano) does not induce adverse immunostimulation, in contrast to its predecessor, ETC-216, which was thought to contain host cell proteins (HCPs) that elicited an inflammatory reaction.

Methods: Data were taken from a clinical trial in which 24 healthy volunteers (HV) and 24 patients with proven stable coronary artery disease (sCAD) received a single intravenous dose of MDCO-216, ranging 5-40 mg/kg. Additionally, whole blood from 35 HV, 35 sCAD patients and 35 patients requiring acute coronary intervention (aCAD group) was stimulated ex vivo with MDCO-216 and ETC-216.

Impact of pre-existing or new-onset atrial fibrillation on 30-day clinical outcomes following transcatheter aortic valve replacement: Results from the BRAVO 3 randomized trial.

Background: Prior studies have suggested that patients with atrial fibrillation (AF) undergoing transcatheter aortic valve replacement (TAVR) are at higher risk for adverse cardiovascular events. Whether procedural bivalirudin compared with unfractionated heparin (UFH) has a beneficial effect on early outcomes in these patients is unknown. We examined for the effect of baseline or new-onset AF within 30 days of TAVR and explored for the effect of bivalirudin versus UFH by AF status, on 30-day outcomes from the BRAVO 3 trial.

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.

Background: In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers.

Methods: We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran.

A Highly Durable RNAi Therapeutic Inhibitor of PCSK9.

Background: Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol.

Methods: In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated.

Persistent changes in lipoprotein lipids after a single infusion of ascending doses of MDCO-216 (apoA-IMilano/POPC) in healthy volunteers and stable coronary artery disease patients.

Background And Aims: Effects of single ascending doses of MDCO-216 on plasma lipid and lipoprotein levels were assessed in human healthy volunteers and in patients with stable coronary artery disease (CAD).

Methods: MDCO-216 was infused at a single dose of 5, 10, 20, 30 or 40 mg/kg over 2 h and blood was collected at 2, 4, 8, 24, 48, 168 and 720 h after start of infusion (ASOI). Lipoprotein lipids were assessed by FLPC and by 1H NMR.

A single infusion of MDCO-216 (ApoA-1 Milano/POPC) increases ABCA1-mediated cholesterol efflux and pre-beta 1 HDL in healthy volunteers and patients with stable coronary artery disease.

Aims: Apolipoprotein A-1 (ApoA-1), based on epidemiology, is inversely associated with cardiovascular (CV) events. Human carriers of the ApoA-1 Milano variant have a reduced incidence of CV disease. Regression of atherosclerotic plaque burden was previously observed on intravascular ultrasound (IVUS) with ETC-216, a predecessor of MDCO-216.