GSK3389404 / GSK, Ionis - LARVOL DELTA

Nonclinical phenotypic evaluation of clinically identified baseline and treatment-emergent hepatitis B Virus variants that contain single nucleotide polymorphisms in the bepirovirsen binding site (EASL-ILC 2024) - P2b | "Clinically identified baseline (BL) HBV variants were previously evaluated nonclinically for their susceptibility to the GalNAc-conjugated form of BPV, GSK3389404, in primary human hepatocytes (PHH) and to BPV in the case of HBV variant C9A using the RNA Launch model. Using our two-step system of HepG2 and PHH, we evaluated the susceptibility of clinically identified HBV BL and TE variants containing SNPs in the BPV site to BPV. The biological basis for varying levels of fitness of each variant, through potential impact of SNPs on HBx and HBV DNA polymerase function, is under evaluation. While the frequency of these HBV variants is very low, the relevance of the in vitro phenotypic data to clinical outcome is subject to further investigation."

Clinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A primary human hepatocyte system to evaluate antisense oligonucleotide activity against clinically identified hepatitis b virus variants that contain mismatches in the bepirovirsen binding site (EASL-ILC 2023) - P2b | "Background and Aims: Bepirovirsen (BPV; GSK3228836) and GSK3389404, a GalNAc conjugated BPV, are anti-sense oligonucleotides (ASO) that target a conserved 20 nucleotide sequence present within all hepatitis B virus (HBV) mRNAs, including pgRNA. We have developed a two-step in vitro model to provide an estimate of replicative fitness and evaluate ASO susceptibility of HBV variants with a SNP in the BPV binding site. Using this system, a few HBV variants identified from B-Clear baseline samples were evaluated. Clinical relevance of HBV variants with reduced susceptibility is under investigation."

Clinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Antisense oligodeoxynucleotides: the certain but limited efficacy and the uncovering mechanisms for the cure of chronic hepatitis B (PubMed, Zhonghua Gan Zang Bing Za Zhi) - "Particularly in the report of phase IIb clinical trial of Bepirovirsen (GSK3228836), approximately 9-10% patients with low baseline serum HBsAg (> 100 IU/ml & < 3 000 IU/ml) achieved functional cure after 24 weeks' of Bepirovirsen treatment. After reviewing the results of other clinical trials, one would be impressed to know that ALG-020572 (Aligos), RO7062931 (Roche) and GSK3389404 (GSK) all failed to sufficiently suppress serum HBsAg expression though the hepatocyte-targeted delivery of these ASOs were enhanced via N-acetyl galactosamine conjugation...Eventually the serum HBsAg declines in most participants and even disappears in a small fraction of patients with low baseline HBsAg level, via attack the infected hepatocytes evidenced by the aberrant elevation of ALT. Nevertheless, the functional cure of CHB remains a challenging issue and more efforts are needed."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Comparison of Pharmacokinetics of the GalNAc-Conjugated Antisense Oligonucleotide GSK3389404 in Participants with Chronic Hepatitis B Infection across the Asia-Pacific Region. (PubMed, Antimicrob Agents Chemother) - P2 | "The GSK3389404 plasma concentration versus time profiles, half-life, t, C, and AUC values were all comparable across the Asia-Pacific populations. Given the similarity of the PK among ASOs, this analysis suggests that the PK from any Asia-Pacific population may be used to guide ASO dose selection in the Asia-Pacific region."

Clinical • Journal • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Reply to: Bepirovirsen / GSK3389404: antisense or TLR9 agonists? (PubMed, J Hepatol) - No abstract available

Journal

Bepirovirsen / GSK3389404: antisense or TLR9 agonists? (PubMed, J Hepatol) - No abstract available

Journal

Bepirovirsen, antisense oligonucleotide (ASO) against hepatitis B virus (HBV), harbors intrinsic immunostimulatory activity via Toll-like receptor 8 (TLR8) preclinically, correlating with clinical efficacy from the Phase 2a study (EASL-ILC 2022) - P2 | "Background and aims: Bepirovirsen (BPV) is a modified ASO targeting HBV RNAs including pregenomic RNA; GSK3389404 (GSK404) is GalNac conjugated BPV. TLR8 agonism of BPV was confirmed preclinically. Cytokines/chemokines changed by BPV treatment in the Phase 2a study indicate that an immunostimulatory activity of BPV via TLR8 may be correlated with ASO-mediated HBsAg reduction. These findings support further investigation of a combination of HBsAg reducing agent and TLR8 agonist for treating HBV."

P2a data • Preclinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNG • IL1R1 • TLR8

Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy. (PubMed, J Hepatol) - P2 | "GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified."

Journal • P2a data • Gastrointestinal Cancer • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Liver Cancer • Oncology • Solid Tumor

A Randomized, Double-Blind, Placebo-Controlled, First-Time-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects. (PubMed, Clin Pharmacol Drug Dev) - "In the pooled urine, GSK3389404 was estimated to account for <0.1% of the total dose. In summary, GSK3389404 dosing has been tested up to 120 mg for 4 weeks with an acceptable safety and pharmacokinetic profile, supporting further clinical investigation in patients with chronic hepatitis B."

Clinical • Journal • PK/PD data • Immunology

A Study to Assess the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK3389404 in Chronic Hepatitis B (CHB) Subjects (clinicaltrials.gov) - P2; N=78; Completed; Sponsor: GlaxoSmithKline; Active, not recruiting ➔ Completed

Clinical • Trial completion • F2

RESULTS AFTER 12 WEEKS TREATMENT OF MULTIPLE DOSES OF GSK3389404 IN CHRONIC HEPATITIS B (CHB) SUBJECTS ON STABLE NUCLEOS(T)IDE THERAPY IN A PHASE 2a DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY (AASLD 2019) - P2; "GSK404 had an acceptable safety profile and showed target engagement with dose-dependent declines in mean HBsAg. The Phase 2a study is ongoing with subjects in an optional post-treatment period."

Clinical • P2a data

A Study to Assess the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK3389404 in Chronic Hepatitis B (CHB) Subjects (clinicaltrials.gov) - P2; N=78; Active, not recruiting; Sponsor: GlaxoSmithKline; Recruiting ➔ Active, not recruiting; Phase classification: P1/2 ➔ P2; N=150 ➔ 78

Clinical • Enrollment change • Enrollment closed • Phase classification

A Study to Assess the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK3389404 in Chronic Hepatitis B (CHB) Subjects (clinicaltrials.gov) - P1/2; N=150; Recruiting; Sponsor: GlaxoSmithKline; Phase classification: P2 ➔ P1/2; Trial completion date: Jan 2019 ➔ Nov 2019

Clinical • Phase classification • Trial completion date