Lack of Pharmacokinetic Drug-Drug Interactions Between Bepirovirsen and Nucleos(t)ide Analogs.

Bepirovirsen is an antisense oligonucleotide currently in Phase 3 development to treat chronic hepatitis B virus (HBV) infection. Given the importance of coadministration of bepirovirsen and standard-of-care nucleos(t)ide analogs (NAs), we evaluated drug-drug interactions (DDIs) between bepirovirsen, entecavir (ETV), and tenofovir (TFV) using in vitro and clinical data obtained through innovative study design and sampling strategy. Static models employing in vitro data indicated that bepirovirsen is not a direct inhibitor or inducer of most drug-metabolizing enzymes or an inhibitor or substrate of drug transporters and poses no clinical DDI risk against NAs.

Pharmacologic evaluation of delayed long-acting cabotegravir administration among cisgender women in HPTN 084.

Unlabelled: HPTN 084 demonstrated the superiority of long-acting injectable cabotegravir (CAB-LA) compared with daily oral tenofovir disoproxil fumarate-emtricitabine (F/TDF) for HIV prevention in women. CAB-LA (600 mg) or placebo injections were administered 4 weeks after an initial dose (loading dose) and every 2 months (Q2M) thereafter; this is the approved regimen. Participants experienced both loading dose and Q2M delays during the trial.

A Phase 1, Single-Dose Study to Evaluate the Pharmacokinetics and Safety of Bepirovirsen in Adults with Hepatic Impairment and Healthy Participants (B-Assured).

Bepirovirsen is a developmental antisense oligonucleotide (ASO) for treatment of chronic hepatitis B virus infection. No pharmacokinetic (PK) studies comparing participants with hepatic impairment (HI) and healthy participants (HPs) have been conducted with ASOs. Given the target patient population, characterization of bepirovirsen PK in HI was imperative.

Population Pharmacokinetics of Bepirovirsen in Healthy Participants and Participants with Chronic Hepatitis B Virus Infection: Results from Phase 1, 2a, and 2b Studies.

Introduction: Bepirovirsen is a novel antisense oligonucleotide in development for chronic hepatitis B virus (HBV) infection therapy. Understanding the impact that clinical characteristics may have on bepirovirsen exposure is important for determining efficacious and well-tolerated dosing regimens. This analysis evaluated demographics and clinical characteristics associated with bepirovirsen exposure using a population pharmacokinetic (PK) analysis.

Long-acting cabotegravir pharmacokinetics with and without oral lead-in for HIV PrEP.

Unlabelled: Long-acting cabotegravir is approved for pre-exposure prophylaxis and combination HIV treatment, both initiated with optional short-term oral lead-in (OLI). We evaluated the impact of OLI on long-acting cabotegravir pharmacokinetics. Cabotegravir plasma concentrations were compared between HIV-positive participants initiating injections with ( = 278) or without ( = 110) OLI in phase III treatment study FLAIR and in HIV-negative participants using OLI ( = 263) in pivotal pre-exposure prophylaxis studies HPTN 083 and HPTN 084.

Comparison of Pharmacokinetics of the GalNAc-Conjugated Antisense Oligonucleotide GSK3389404 in Participants with Chronic Hepatitis B Infection across the Asia-Pacific Region.

GSK3389404, an N-acetyl galactosamine-conjugated antisense oligonucleotide (ASO), was in clinical development for chronic hepatitis B (CHB) treatment. Few studies have examined ASOs in Asian participants. In this analysis, the plasma pharmacokinetics (PK) of GSK3389404 were characterized and compared in patients with CHB across the Asia-Pacific region (N = 64), including mainland China ( = 16), Hong Kong ( = 8), Japan ( = 21), South Korea ( = 12), Singapore ( = 4), and the Philippines ( = 3), from a phase 2a, multicenter, randomized, double-blind, placebo-controlled study (NCT03020745).

Preclinical and Phase 1 Assessment of Antisense Oligonucleotide Bepirovirsen in Hepatitis B Virus-Transgenic Mice and Healthy Human Volunteers: Support for Clinical Dose Selection and Evaluation of Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses.

Dose-dependent reductions in hepatitis B virus (HBV) RNA, DNA, and viral proteins following bepirovirsen administration were observed in HepG2.2.15 cells.

Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy.

Background & Aims: Bepirovirsen, an antisense oligonucleotide targeting pregenomic and mRNA transcripts of HBV, has been conjugated to N-acetyl galactosamine (GSK3389404) to enhance hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 for chronic HBV infection.

Methods: This phase IIa, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745).

Safety, Tolerability, Pharmacokinetics, and Acceptability of Oral and Long-Acting Cabotegravir in HIV-Negative Chinese Men.

Long-acting (LA) cabotegravir demonstrated superior efficacy versus daily oral standard-of-care for HIV-1 preexposure prophylaxis. This phase 1 study assessed safety, tolerability, pharmacokinetics, and acceptability of cabotegravir in 47 HIV-negative adult Chinese men at low risk of acquiring HIV-1. Participants received once-daily oral cabotegravir 30 mg for 4 weeks and, after a 1-week washout, five 600-mg (3-mL) intramuscular cabotegravir LA injections at weeks 5, 9, 17, 25, and 33.

Randomized clinical trials towards a single-visit cure for chronic hepatitis C: Oral GSK2878175 and injectable RG-101 in chronic hepatitis C patients and long-acting injectable GSK2878175 in healthy participants.

Single-visit cures for chronic hepatitis C are lacking. We conducted two clinical studies towards the goal of developing a regimen for single-visit cure. In a randomized, open-label, Phase 2 study (RG101-04), investigators enrolled 26 adult chronic hepatitis C patients to evaluate safety and efficacy of single subcutaneous injection of RG-101 (4 mg/kg) and daily oral tablets of GSK2878175 (20 mg) for 6, 9 or 12 weeks.

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.

GSK3389404 is a liver-targeted antisense oligonucleotide that inhibits synthesis of hepatitis B surface antigen and all other hepatitis B virus proteins. This first-in-human, randomized, double-blind, phase 1 study assessed the safety and pharmacokinetics of GSK3389404 administered subcutaneously (SC) in healthy subjects. Four single ascending-dose cohorts (10 mg, 30 mg, 60 mg, and 120 mg) and 3 multiple ascending-dose cohorts (30 mg, 60 mg, and 120 mg once weekly for 4 weeks) each comprised 6 subjects randomized to GSK3389404 and 2 subjects randomized to placebo.

Exposure-Response and Tumor Growth Inhibition Analyses of the Monovalent Anti-c-MET Antibody Onartuzumab (MetMAb) in the Second- and Third-Line Non-Small Cell Lung Cancer.

The phase III trial comparing onartuzumab + erlotinib vs. erlotinib in the second- and third-line non-small cell lung cancer (NSCLC) did not meet its primary endpoint of overall survival (OS). The objective was to assess whether doses higher than the phase III dose (15 mg/kg) might yield better efficacy without compromising the safety profile.

Modeling and simulation of maintenance treatment in first-line non-small cell lung cancer with external validation.

Background: Maintenance treatment (MTx) in responders following first-line treatment has been investigated and practiced for many cancers. Modeling and simulation may support interpretation of interim data and development decisions. We aimed to develop a modeling framework to simulate overall survival (OS) for MTx in NSCLC using tumor growth inhibition (TGI) data.

Simulations to Predict Clinical Trial Outcome of Bevacizumab Plus Chemotherapy vs. Chemotherapy Alone in Patients With First-Line Gastric Cancer and Elevated Plasma VEGF-A.

To simulate clinical trials to assess overall survival (OS) benefit of bevacizumab in combination with chemotherapy in selected patients with gastric cancer (GC), a modeling framework linking OS with tumor growth inhibition (TGI) metrics and baseline patient characteristics was developed. Various TGI metrics were estimated using TGI models and data from two phase III studies comparing bevacizumab plus chemotherapy vs. chemotherapy as first-line therapy in 976 GC patients.