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The purpose of this study is to characterize the population pharmacokinetics (popPK) of subcutaneous (SC) daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone and explore the relationship between daratumumab systemic exposure and selected efficacy and safety end points in patients with newly diagnosed systemic amyloid light‐chain amyloidosis. The popPK analysis included pharmacokinetic and immunogenicity data from patients receiving daratumumab SC in combination with bortezomib, cyclophosphamide, and dexamethasone in the ANDROMEDA study (AMY3001; safety run‐in, n = 28; randomized phase, n = 183). Nonlinear mixed‐effects modeling was used to characterize the popPK and quantify the impact of potential covariates. The exposure‐response (E‐R) analysis included data from all patients in the randomized phase of ANDROMEDA (n = 388). Logistic regression and survival analysis were used to evaluate the relationships between daratumumab systemic exposure and efficacy end points. The E‐R analysis on safety was conducted using quartile comparison and logistic regression analysis. The observed concentration‐time data of daratumumab SC were well described by a 1‐compartment popPK model with first‐order absorption and parallel linear and nonlinear Michaelis‐Menten elimination pathways. None of the investigated covariates were determined to be clinically meaningful. Daratumumab systemic exposure was generally similar across subgroups that achieved different levels of hematologic response, and there was no apparent relationship between daratumumab systemic exposure and the investigated safety end points. In conclusion, the popPK and E‐R analyses supported the selected 1800‐mg flat dose of daratumumab SC in combination with the bortezomib, cyclophosphamide, and dexamethasone regimen for the treatment of light‐chain amyloidosis. No dose adjustment was recommended for investigated covariates. [ABSTRACT FROM AUTHOR]

The safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of JNJ‑61178104, a novel anti–tumor necrosis factor‐alpha (TNFα) and anti–interleukin‐17A (IL‑17A) bispecific antibody, were investigated in a placebo‐controlled, first‐in‐human study. Healthy subjects (n = 54) received a single dose of JNJ‐61178104 by either intravenous infusion (0.1, 0.3, 1, 3, and 10 mg/kg) or subcutaneous injection (1 mg/kg). Blood samples for measurement of serum JNJ‐61178104 concentrations, total IL‐17A, total TNFα, and detection of antidrug antibodies were collected for up to 16 weeks after dosing and assessed using electrochemiluminescence immunoassays. PK parameters were calculated by noncompartmental analysis and estimated by nonlinear mixed‐effects modeling. JNJ‐61178104 was generally well tolerated in healthy subjects. For the intravenous cohorts, mean maximum concentration, and area under the concentration‐time curve values increased in a dose‐proportional manner. Mean clearance ranged from 6.73 to 9.99 mL/day/kg, mean volume of distribution at terminal phase after intravenous administration ranged from 51.0 to 91.9 mL/kg, and mean half‐life ranged from 4.3 to 9.7 days following intravenous administration. After a single subcutaneous dose of 1 mg/kg, median time to maximum concentration was 4.0 days, mean bioavailability was 52.0% and mean half‐life was 5.3 days. A linear 2‐compartment population model with first‐order elimination adequately characterized the pharmacokinetics with parameters consistent with noncompartmental analysis estimates. Body weight and antidrug antibodies were significant covariates on JNJ‐61178104 clearance. The time to reach mean maximum serum total TNFα and total IL‐17A concentrations appeared to be dose dependent across the 0.1 mg/kg to 10 mg/kg IV dose groups. All subjects who received active treatment were antidrug antibody positive after dosing with JNJ‐61178104. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the pharmacokinetics and safety of single intravenous doses of JNJ-54452840 infused over 1 minute in healthy male Japanese and Caucasian participants. JNJ-54452840 is a novel peptide for the treatment of chronic heart failure, with a proposed mechanism of action of binding interference and decreased production of anti-β1-adrenergic receptor (anti-β1-AR) antibodies, which stimulate the cardiac β1-AR.Methods: In this randomized, single-centre, double-blind, placebo-controlled, four-way crossover study, 32 male Japanese and Caucasian participants (16 in each group) received single intravenous doses of JNJ-54452840 20, 80 and 240 mg, and placebo, each separated by a ≥7-day washout period. Pharmacokinetics and safety were assessed predose and at specified timepoints for 24 h. Anti-β1-AR antibodies were monitored.Results: The mean JNJ-54452840 maximum observed plasma concentration (C max) and area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase (AUCinf) values increased linearly with dose, with rapid elimination in both groups. Dose proportionality criteria were not met between the 20 and 240 mg doses for both study cohorts. The median time to reach C max (T max) ranged from 1 to 5 minutes. The mean total systemic clearance after intravenous administration (CL), volume of distribution at steady state (V ss), mean residence time (MRT) and terminal half-life (T ½) values were similar for both groups. The mean T ½ values ranged from 5.9 to 26.1 min in a dose-dependent manner. The overall prevalence of antibodies was 9.4 % at baseline; antibodies not present at baseline developed in five Caucasians (15.6 %) but not in Japanese participants. One participant in each group experienced a serious thromboembolic event (pulmonary embolism, ischaemic stroke).Conclusion: JNJ-54452840 demonstrated similar pharmacokinetics in both groups. JNJ-54452840 was possibly immunogenic, and two participants reported thromboembolic serious adverse events. The relationship between these events and antibody formation is not known. [ABSTRACT FROM AUTHOR]

Objective: Interleukin (IL)-12 and IL-23 have been implicated in the pathogenesis of rheumatoid arthritis (RA). The safety and efficacy of ustekinumab, a human monoclonal anti-IL-12/23 p40 antibody, and guselkumab, a human monoclonal anti-IL-23 antibody, were evaluated in adults with active RA despite methotrexate (MTX) therapy.Methods: Patients were randomly assigned (1:1:1:1:1) to receive placebo at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 12 weeks (n=55), guselkumab 50 mg at weeks 0, 4 and every 8 weeks (n=55), or guselkumab 200 mg at weeks 0, 4 and every 8 weeks (n=54) through week 28; all patients continued a stable dose of MTX (10-25 mg/week). The primary end point was the proportion of patients with at least a 20% improvement in the American College of Rheumatology criteria (ACR 20) at week 28. Safety was monitored through week 48.Results: At week 28, there were no statistically significant differences in the proportions of patients achieving an ACR 20 response between the combined ustekinumab group (53.6%) or the combined guselkumab group (41.3%) compared with placebo (40.0%) (p=0.101 and p=0.877, respectively). Through week 48, the proportions of patients with at least one adverse event (AE) were comparable among the treatment groups. Infections were the most common type of AE.Conclusions: Treatment with ustekinumab or guselkumab did not significantly reduce the signs and symptoms of RA. No new safety findings were observed with either treatment.Trial Registration Number: NCT01645280. [ABSTRACT FROM AUTHOR]