Inhibiting the alternative pathway of complement by reducing systemic complement factor B: Randomized, double-blind, placebo-controlled phase 1 studies with Sefaxersen.

An over-active alternative complement pathway has been implicated in the pathophysiology of multiple diseases, including IgA nephropathy and geographic atrophy secondary to age related macular degeneration. In first-in-human double-blind, placebo-controlled phase 1 studies, the safety and pharmacodynamic effects of sefaxersen (RO7434656), a GalNAc-conjugated 2'-MOE antisense oligonucleotide targeting the complement factor B mRNA, was investigated. Healthy volunteers received either single or repeated (for 6 weeks) subcutaneous administrations of investigational drug or placebo.

Safety and Tolerability of GalNAc-Conjugated Antisense Drugs Compared to the Same-Sequence 2'--Methoxyethyl-Modified Antisense Drugs: Results from an Integrated Assessment of Phase 1 Clinical Trial Data.

The triantennary -acetylgalactosamine (GalNAc) cluster has demonstrated the utility of receptor-mediated uptake of ligand-conjugated antisense drugs targeting RNA expressed by hepatocytes. GalNAc-conjugated 2'--methoxyethyl (2'MOE) modified antisense oligonucleotides (ASOs) have demonstrated a higher potency than the unconjugated form to support lower doses for an equivalent pharmacological effect. We utilized the Ionis integrated safety database to compare four GalNAc-conjugated and four same-sequence unconjugated 2'MOE ASOs.

Predicting the pharmacokinetics and pharmacodynamics of antisense oligonucleotides: an overview of various approaches and opportunities for PBPK/PD modelling.

Introduction: Advances in research and development (R&D) have enabled many approvals of antisense oligonucleotides (ASOs). Its administration expanded from systemic to local for treating various diseases, where predicting target tissue exposures and pharmacokinetics (PK) and pharmacodynamics (PD) in human can be critical.

Areas Covered: A literature search for PBPK/PD models of ASOs was conducted using PubMed and Embase (to 1 April 2023).

Integrated Assessment of Phase 2 Data on GalNAc-Conjugated 2'--Methoxyethyl-Modified Antisense Oligonucleotides.

Receptor-mediated delivery of an antisense oligonucleotide (ASO) using the ligand-conjugated antisense technology is establishing a new benchmark for antisense therapeutics. The triantennary -acetylgalactosamine (GalNAc) cluster is the first conjugated ligand to yield a marked increase in ASO potency for RNA targets expressed by hepatocytes, compared to the unconjugated form. In this study, we present an integrated safety assessment of data available from randomized, placebo-controlled, phase 2 studies for six GalNAc-conjugated 2'--methoxyethyl (2'MOE)-modified ASOs.

Assessment of efficacy and safety of volanesorsen for treatment of metabolic complications in patients with familial partial lipodystrophy: Results of the BROADEN study: Volanesorsen in FPLD; The BROADEN Study.

Background: Volanesorsen, an antisense oligonucleotide, is designed to inhibit hepatic apolipoprotein C-III synthesis and reduce plasma apolipoprotein C-III and triglyceride concentrations.

Objective: The present study assessed efficacy and safety of volanesorsen in patients with familial partial lipodystrophy (FPLD) and concomitant hypertriglyceridemia and diabetes.

Methods: BROADEN was a randomized, placebo-controlled, phase 2/3, 52-week study with open-label extension and post-treatment follow-up periods.

Assessment of the Effect of Organ Impairment on the Pharmacokinetics of 2'-MOE and Phosphorothioate Modified Antisense Oligonucleotides.

The pharmacokinetics (PK) of 2'-O-methoxyethyl and phosphorothioate antisense oligonucleotides (ASOs), with or without N-acetyl galactosamine conjugation, have been well characterized following subcutaneous or intravenous drug administration. However, the effect of organ impairment on ASO PK, primarily hepatic or renal impairment, has not yet been reported. ASOs distribute extensively to the liver and kidneys, where they are metabolized slowly by endo- and exonucleases, with minimal renal excretion as parent drug (<1%-3%).

Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXI in Patients With ESRD.

Introduction: Patients with end-stage renal disease (ESRD) requiring hemodialysis (HD) have an increased risk of thrombotic events and bleeding. Antisense reduction of factor XI (FXI) with IONIS-FXI is a novel strategy that may safely reduce the risk of thrombotic events.

Methods: This multicenter study enrolled 49 patients receiving HD in 2 parts.

Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk.

Aims: Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease.

Methods And Results: A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200-500 mg/dL (2.

Improvements in the Tolerability Profile of 2'--Methoxyethyl Chimeric Antisense Oligonucleotides in Parallel with Advances in Design, Screening, and Other Methods.

The development process of antisense oligonucleotides (ASOs) as therapeutic agents in humans has advanced through the implementation of chemical compound modifications as well as increasingly sophisticated toxicological preclinical screening techniques. The Ionis Integrated Safety Database was utilized to determine if advances in ASO screening and clinical lead identification methods have improved the tolerability profiles of 2'--methoxyethyl (2'MOE)-modified ASOs as a class, relative to the first 2'MOE ASO approved for use in humans, mipomersen. Tolerability was assessed by the incidence and percentage of subcutaneous doses leading to adverse events at the injection site or flu-like reactions (FLRs), as well as by the incidence of dose discontinuations due to these events.

Antisense Inhibition of Angiotensinogen With IONIS-AGT-L: Results of Phase 1 and Phase 2 Studies.

Targeting angiotensinogen (AGT) may provide a novel approach to more optimally inhibit the renin-angiotensin-aldosterone system pathway. Double-blind, placebo-controlled clinical trials were performed in subjects with hypertension as monotherapy or as an add-on to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with IONIS-AGT-L versus placebo up to 2 months. IONIS-AGT-L was well tolerated with no significant changes in platelet count, potassium levels, or liver and renal function.

PK/PD modeling of FXI antisense oligonucleotides to bridge the dose-FXI activity relation from healthy volunteers to end-stage renal disease patients.

IONIS-FXI (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI (FXI) and has been investigated in healthy volunteers and patients with end-stage renal disease (ESRD). FXI-LICA (BAY2976217) shares the same RNA sequence as IONIS-FXI but contains a GalNAc-conjugation that facilitates asialoglycoprotein receptor (ASGPR)-mediated uptake into hepatocytes. FXI-LICA has been studied in healthy volunteers and is currently investigated in patients with ESRD on hemodialysis.

Interspecies Scaling of Human Clearance and Plasma Trough Exposure for Antisense Oligonucleotides: A Retrospective Analysis of GalNAc3-Conjugated and Unconjugated-Antisense Oligonucleotides.

It is well documented and generally accepted that human clearance (CL) of unconjugated single-strand antisense oligonucleotides (ASOs) can be directly predicted from monkeys by body weight (BW) on a mg/kg dose basis. However, the scaling for triantennary -acetyl galactosamine (GalNAc)-conjugated ASOs has not been fully established. In this study, we retrospectively analyzed pharmacokinetic data from 9 GalNAc-conjugated and 12 unconjugated single-stranded ASOs (ten 2'-methoxyethyl and two 2', 4'-constrained ethyl ASOs) to identify an appropriate allometric scaling factor between the two species.

Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data.

Aims: Amyloidogenic transthyretin (ATTR) amyloidosis is a fatal disease characterized by progressive cardiomyopathy and/or polyneuropathy. AKCEA-TTR-L (ION-682884) is a ligand-conjugated antisense drug designed for receptor-mediated uptake by hepatocytes, the primary source of circulating transthyretin (TTR). Enhanced delivery of the antisense pharmacophore is expected to increase drug potency and support lower, less frequent dosing in treatment.

Antisense Inhibition of Prekallikrein to Control Hereditary Angioedema.

Hereditary angioedema is characterized by recurrent and unpredictable episodes of subcutaneous and mucosal swelling that can be life threatening. IONIS-PKK-L is a ligand-conjugated antisense oligonucleotide designed for receptor-mediated delivery to hepatocytes. In a compassionate-use pilot study, two patients with severe bradykinin-mediated angioedema were initially administered weekly subcutaneous injections of the unconjugated parent drug, IONIS-PKK, for 12 to 16 weeks, after which they received IONIS-PKK-L at a dose of 80 mg every 3 to 4 weeks for 7 to 8 months.

Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia.

Aims: Loss-of-function mutations in ANGPTL3 are associated with beneficial effects on lipid and glucose metabolism and reduced risk of coronary artery disease. Vupanorsen (AKCEA-ANGPTL3-L Rx ) is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits angiopoietin-like 3 (ANGPTL3) protein synthesis.

Methods And Results: This was a double-blind, placebo-controlled, dose-ranging, Phase 2 study.

Immunogenicity Assessment of Inotersen, a 2'--(2-Methoxyethyl) Antisense Oligonucleotide in Animals and Humans: Effect on Pharmacokinetics, Pharmacodynamics, and Safety.

Inotersen (TEGSEDI™) is a 2'--(2-methoxyethyl)-modified antisense oligonucleotide, intended for treating hereditary transthyretin (TTR) amyloidosis with polyneuropathy. The potential immunogenicity (IM) response to inotersen was evaluated in chronic nonclinical safety studies and the pivotal phase 2/3 clinical study. The evaluation was designed to assess the characteristics of antidrug antibodies (ADAs) and their effects on the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety in animals and humans.

Antisense drug discovery and development technology considered in a pharmacological context.

When coined, the term "antisense" included oligonucleotides of any structure, with any chemical modification and designed to work through any post-RNA hybridization mechanism. However, in practice the term "antisense" has been used to describe single stranded oligonucleotides (ss ASOs) designed to hybridize to RNAswhile the term "siRNA" has come to mean double stranded oligonucleotides designed to activate Ago2. However, the two approaches share many common features.

Treatment with Volanesorsen, a 2'-O-Methoxyethyl-Modified Antisense Oligonucleotide Targeting mRNA, Does Not Affect the QTc Interval in Healthy Volunteers.

The aim of this study was to assess the effect of volanesorsen on the corrected QT (QTc) interval. This thorough QT study enrolled 52 healthy male and female subjects who were randomized at a single site in a four-way crossover study. Subjects were randomly assigned to 1 of 12 treatment sequences and crossed over into four treatment periods over the course of which each subject was to receive a single therapeutic dose of volanesorsen as a 300 mg subcutaneous (SC) injection, a single supratherapeutic dose of volanesorsen as 300 mg intravenous (IV) infusion, a single oral (PO) dose of moxifloxacin (positive control), and placebo dose.

Novel antisense inhibition of diacylglycerol O-acyltransferase 2 for treatment of non-alcoholic fatty liver disease: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

Background: Diacylglycerol-O-acyltransferase 2 (DGAT2) is one of two enzyme isoforms that catalyse the final step in the synthesis of triglycerides. IONIS-DGAT2 is an antisense oligonucleotide inhibitor of DGAT2 that is under clinical investigation for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The aim of this trial was to examine the safety, tolerability, and efficacy of IONIS-DGAT2 versus placebo in reducing liver fat in patients with type 2 diabetes and NAFLD.

Population Pharmacokinetic-Pharmacodynamic Modeling of Inotersen, an Antisense Oligonucleotide for Treatment of Patients with Hereditary Transthyretin Amyloidosis.

A population pharmacokinetic (PK) and pharmacodynamic (PD) model was developed for inotersen to evaluate exposure-response relationships and to optimize therapeutic dosing regimen in patients with hereditary transthyretin (TTR) amyloidosis polyneuropathy (hATTR-PN). Inotersen PK and TTR level (PD) data were composed of one Phase 1 study in healthy subjects, one Phase 2/3 study in hATTR patients, and its one open-label extension study. Effects of intrinsic and extrinsic factors (covariates) on PK and PK/PD of inotersen were evaluated using a full model approach.