Recombinant Alpha-1 Antitrypsin-Fc Fusion Protein INBRX-101 in Adults With Alpha-1 Antitrypsin Deficiency: A Phase 1 Study.

Background: Alpha-1 antitrypsin deficiency (AATD) is characterized by low alpha-1 antitrypsin (AAT) levels, predisposing individuals to lung disease. The standard of care, plasma-derived AAT (pdAAT), is delivered as weekly infusions to maintain serum AAT concentrations ≥11µM (≈50% of those in healthy individuals). INBRX-101, a recombinant human AAT-Fc fusion protein, was designed to have a longer half-life and achieve higher AAT levels than pdAAT.

Safety, Pharmacokinetics and Preliminary Efficacy of IL4-Rα Monoclonal Antibody AK120 in Both Healthy and Atopic Dermatitis Subjects: A Phase I, Randomized, Two-Part, Double-Blind, Placebo-Controlled, Dose-Escalation, First-In-Human Clinical Study.

Introduction: Interleukin-4 (IL-4) and interleukin-13 (IL-13) are two essential cytokines involved in the T helper 2 (Th2)-mediated inflammatory response to diseases, such as atopic dermatitis (AD). AK120 is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) directed against the IL-4 receptor alpha (IL-4Rα) subunit shared by the IL-4 and IL-13 receptor complexes. This mAb inhibits the signaling of the IL-4 and IL-13 cytokines.

First-in-human phase 1 trial evaluating safety, pharmacokinetics, and pharmacodynamics of NLRP3 inflammasome inhibitor, GDC-2394, in healthy volunteers.

Inappropriate and chronic activation of the cytosolic NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first-in-human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150-1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC-2394, a small-molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC-2394 and its CYP3A4 induction potential in food-effect (FE) and drug-drug interaction (DDI) stages, respectively.

A randomized, double-blind, single-dose study to assess bioequivalence of MB02 biosimilar after manufacturing iteration and reference bevacizumab.

To investigate and compare the pharmacokinetic (PK) profiles of MB02 products, before and after optimizing the manufacturing process, and reference bevacizumab to establish bioequivalence between them. In this randomized, double-blind, single dose, parallel study, 114 healthy male volunteers were randomized 1:1:1 to receive a 1 mg/kg intravenous dose of MB02-SP, MB02-DM, or US-bevacizumab. The follow-up period was 100 days.

Pharmacokinetics and pharmacodynamics of a proposed tocilizumab biosimilar MSB11456 versus both the US-licensed and EU-approved products: a randomized, double-blind trial.

Background: Tocilizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody against the interleukin-6 receptor (IL-6 R). MSB11456 is a proposed tocilizumab biosimilar.

Objectives: To assess the pharmacokinetic and pharmacodynamic similarity of MSB11456 to both US-licensed and EU-approved tocilizumab.

Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC-0214 in healthy volunteers.

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo-controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC-0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule-based inhaler.

A randomized phase I study comparing the pharmacokinetics of a bevacizumab (HD204) biosimilar to European Union- and United States of America-sourced bevacizumab.

Purpose: This first-in-human study was designed to evaluate the pharmacokinetic (PK) equivalence between HD204 and the European Union (EU)-sourced bevacizumab, between HD204 and the United States of America (US)-sourced bevacizumab, and between EU-sourced and US-sourced bevacizumab (NCT03390673).

Methods: In this randomized, double-blind, 3-way parallel group, single-dose comparative PK study, healthy male subjects were randomized to receive a single 1 mg/kg intravenous dose of HD204, EU-sourced bevacizumab or US-sourced bevacizumab. PK parameters were calculated using non-compartmental methods.

Improved technology satisfaction and sleep quality with Medtronic MiniMed® Advanced Hybrid Closed-Loop delivery compared to predictive low glucose suspend in people with Type 1 Diabetes in a randomized crossover trial.

Background: Automated insulin delivery aims to lower treatment burden and improve quality of life as well as glycemic outcomes.

Methods: We present sub-study data from a dual-center, randomized, open-label, two-sequence crossover study in automated insulin delivery naïve users, comparing Medtronic MiniMed® Advanced Hybrid Closed-Loop (AHCL) to Sensor Augmented Pump therapy with Predictive Low Glucose Management (SAP + PLGM). At the end of each 4-week intervention, impacts on quality of life, sleep and treatment satisfaction were compared using seven age-appropriate validated questionnaires given to patients or caregivers.

Improved Glycemic Outcomes With Medtronic MiniMed Advanced Hybrid Closed-Loop Delivery: Results From a Randomized Crossover Trial Comparing Automated Insulin Delivery With Predictive Low Glucose Suspend in People With Type 1 Diabetes.

Objective: To study the MiniMed Advanced Hybrid Closed-Loop (AHCL) system, which includes an algorithm with individualized basal target set points, automated correction bolus function, and improved Auto Mode stability.

Research Design And Methods: This dual-center, randomized, open-label, two-sequence crossover study in automated-insulin-delivery-naive participants with type 1 diabetes (aged 7-80 years) compared AHCL to sensor-augmented pump therapy with predictive low glucose management (SAP + PLGM). Each study phase was 4 weeks, preceded by a 2- to 4-week run-in and separated by a 2-week washout.

Bioavailability of Orally Administered Active Lipid Compounds from four Different Greenshell™ Mussel Formats.

Greenshell™ mussel (GSM, ) is New Zealand's most important aquaculture species. They are a good source of long chain-polyunsaturated fatty acids (-3 LC PUFA). Beyond a traditional food product, GSMs are also sold as mussel powders and oil extract formats in the nutraceutical markets.

Sofosbuvir plus ribavirin and sofosbuvir plus ledipasvir in patients with genotype 1 or 3 hepatitis C virus and severe renal impairment: a multicentre, phase 2b, non-randomised, open-label study.

Background: There is a medical need for highly effective, safe, and well tolerated treatments for patients infected with hepatitis C virus (HCV) with severe renal impairment. We investigated the safety and efficacy of sofosbuvir with ribavirin or ledipasvir combined with sofosbuvir in a prospective study of patients with genotype 1 or 3 HCV infection and stage 4-5 chronic kidney disease (creatinine clearance by Cockcroft-Gault ≤30 mL/min) who were not on dialysis.

Methods: This phase 2b, open-label, non-randomised, multicentre study in the USA and New Zealand investigated three sequentially enrolled cohorts of patients.

Immunogenicity and safety of a proposed pegfilgrastim biosimilar MSB11455 versus the reference pegfilgrastim Neulasta in healthy subjects: A randomized, double-blind trial.

MSB11455 is a proposed biosimilar to the currently licensed reference pegfilgrastim (Neulasta ). This study was designed primarily to compare the immunogenicity of MSB11455 and Neulasta . As secondary objectives, the safety and tolerability of MSB11455 and Neulasta were also compared.

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.

A Global Phase I Clinical Study Comparing the Safety and Pharmacokinetics of Proposed Biosimilar BAT1706 and Bevacizumab (Avastin) in Healthy Male Subjects.

Objective: BAT1706 is a proposed biosimilar of bevacizumab (BEV). The objective of this phase I clinical trial was to establish pairwise similarity between BAT1706, US-sourced BEV (US-BEV), and EU-sourced BEV (EU-BEV) after a single intravenous (IV) infusion in healthy male subjects.

Methods: This phase I clinical trial was a randomized, double-blinded, three-arm study in 128 healthy adult male subjects.

Development of a Subcutaneous Fixed-Dose Combination of Pertuzumab and Trastuzumab: Results From the Phase Ib Dose-Finding Study.

Adding pertuzumab to trastuzumab (both monoclonal antibodies targeting human epidermal growth factor receptor 2 [HER2]) has proven survival benefits when combined with chemotherapy for patients with HER2-positive breast cancer. The combination of pertuzumab and trastuzumab together in 1 vial for subcutaneous (SC) administration is being developed as a ready-to-use formulation to reduce the treatment burden on patients while improving healthcare efficiency. An open-label, 2-part, phase Ib dose-finding study (NCT02738970) was undertaken in healthy male volunteers (part 1) and female patients with HER2-postive early breast cancer who had completed standard (neo)adjuvant treatment (part 2).

A comparative pharmacokinetic study of DRL_BZ, a candidate biosimilar of bevacizumab, with Avastin (EU and US) in healthy male subjects.

Aim: The aim of this study was to compare the pharmacokinetics (PK) of DRL_BZ with that of EU-approved (reference medicinal product; RMP) and US-licensed (reference product; RP) bevacizumab (Avastin ) in healthy male subjects.

Methods: In this double-blind, parallel-group, Phase 1 study (BZ-01-001), men aged 20-45 years were randomized 1:1:1 to receive a single intravenous infusion of 1 mg kg of bevacizumab as DRL_BZ, RMP or RP. A total of 149 subjects were randomized (DRL_BZ, 50; RMP, 50; RP, 49).

Benefit of Apabetalone on Plasma Proteins in Renal Disease.

Introduction: Apabetalone, a small molecule inhibitor, targets epigenetic readers termed BET proteins that contribute to gene dysregulation in human disorders. Apabetalone has and anti-inflammatory and antiatherosclerotic properties. In phase 2 clinical trials, this drug reduced the incidence of major adverse cardiac events in patients with cardiovascular disease.

A randomized, single-blind, Phase I trial (INVICTAN-1) assessing the bioequivalence and safety of BI 695502, a bevacizumab biosimilar candidate, in healthy subjects.

Objectives: This Phase I trial (INVICTAN®-1) evaluated three-way bioequivalence and safety of BI 695502 a bevacizumab biosimilar candidate, and reference product bevacizumab from two sources (US-approved Avastin®, Genentech; EU-approved Avastin, Roche).

Methods: Healthy male subjects (N = 91) were randomized 1:1:1 to receive a single intravenous infusion of 1 mg/kg of BI 695502 or US- or EU-approved Avastin. An interim analysis was planned when ~50% of subjects were evaluable for the primary end point to determine if the prespecified criteria for bioequivalence were achieved; if demonstrated, the study could be stopped early.

Evaluation of Nicotine Pharmacokinetics and Subjective Effects following Use of a Novel Nicotine Delivery System.

Introduction: Novel nicotine delivery systems represent an evolving part of the tobacco harm reduction strategy. The pharmacokinetic (PK) profile of nicotine delivered by P3L, a pulmonary nicotine delivery system, and its effects on smoking urges and craving relief in relation to Nicorette inhalator were evaluated.

Methods: This open-label, ascending nicotine levels study was conducted in 16 healthy smokers.

Effects of Oritavancin on Coagulation Tests in the Clinical Laboratory.

Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid-dependent coagulation tests. The effect of oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study after an infusion of a single 1,200-mg intravenous dose of oritavancin in normal healthy volunteers. Pooled plasma with oritavancin added ex vivo showed concentration-dependent prolongation of prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and dilute Russell viper venom time (DRVVT) test results.

Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection.

Background: In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3.

Methods: We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks.

Pharmacokinetics and Bioavailability of a Fixed-Dose Combination of Ibuprofen and Paracetamol after Intravenous and Oral Administration.

Background And Objectives: Previously published studies have suggested the lack of a pharmacokinetic interaction between ibuprofen and paracetamol when they are delivered as a fixed-dose oral combination. The aim of this study was to determine the pharmacokinetic profile and safety of a fixed-dose intravenous (IV) combination, containing 3 mg/mL ibuprofen and 10 mg/mL paracetamol, in comparison with its individual components. The study also assessed the relative bioavailability of the same doses of the active ingredients when they were administered as an oral formulation.

Investigating clinically adequate concentrations of oseltamivir carboxylate in end-stage renal disease patients undergoing hemodialysis using a population pharmacokinetic approach.

End-stage renal disease (ESRD) patients receiving hemodialysis (HD) are at heightened risk for influenza, but the optimal oseltamivir dosage regimen for treating or preventing influenza in this high-risk population is still uncertain. Pharmacokinetic data for 24 adults with ESRD were pooled from a single-dose and a multiple-dose study to develop a population pharmacokinetic model using nonlinear mixed-effects modeling. The final model comprised five compartments, two each to describe the systemic pharmacokinetics of oseltamivir phosphate and its metabolite, oseltamivir carboxylate (OC), and a delay compartment to describe oseltamivir metabolism.

Comparative pharmacokinetics of subcutaneous trastuzumab administered via handheld syringe or proprietary single-use injection device in healthy males.

Purpose: To demonstrate pharmacokinetic (PK) comparability for a single dose of 600 mg subcutaneous (SC) trastuzumab, administered via a novel single-use injection device (SID) or handheld syringe in 119 randomized healthy male subjects.

Methods: The co-primary PK endpoints area under the time-concentration curve from the start of dosing to day 22 (AUC(0-21 days)) and maximum observed trastuzumab serum concentration (C(max)) were dose-normalized and body-weight-adjusted, and compared using geometric mean ratios (GMRs). SID performance, injection site pain, adverse events, and antidrug antibodies (ADAs) were assessed.