Population pharmacokinetics and exposure-response analyses of daratumumab plus pomalidomide/dexamethasone in relapsed or refractory multiple myeloma.

AIM: A population pharmacokinetic (PPK) model was developed to characterize pharmacokinetics (PK) of subcutaneous or intravenous daratumumab administration in a new indication (i.e., combination with pomalidomide and dexamethasone [D-Pd] in patients with relapsed or refractory multiple myeloma [RRMM]). Analyses were conducted to explore exposure-response (E-R) relationships for efficacy and select treatment-emergent adverse events (TEAEs). METHODS: The PPK analysis included pooled data from the D-Pd cohorts of the phase 3 APOLLO and phase 1b EQUULEUS studies. Covariates were evaluated in the PPK model. Model-predicted exposures to daratumumab were compared between covariate subgroups of interest and used to investigate relationships between daratumumab exposure and efficacy and safety in APOLLO. RESULTS: The PPK analysis included 1146 daratumumab PK samples from 239 patients (APOLLO, n = 140; EQUULEUS, n = 99). Observed concentration-time data of daratumumab were well described by a two-compartment PPK model with first-order absorption and parallel linear and nonlinear elimination pathways. Treatment with D-Pd provided similar daratumumab PK characteristics versus historical daratumumab monotherapy. The E-R dataset contained data from 290 APOLLO patients (D-Pd, n = 140; Pd, n = 150). The PK-efficacy relationship of daratumumab supported improved progression-free survival for patients in the D-Pd group vs. the Pd group. Additionally, TEAEs did not increase with increasing PK exposure in the D-Pd group. CONCLUSIONS: The PPK and E-R analyses support the daratumumab subcutaneous 1800 mg dosing regimen in combination with Pd for treatment of patients with RRMM. No dose adjustment is recommended in this indication for any of the investigated factors, none of which had clinically relevant effects on daratumumab PK.

Development of Therapeutic Proteins for a New Subcutaneous Route of Administration After the Establishment of Intravenous Dosages: A Systematic Review.

Therapeutic proteins may first be developed as intravenous (i.v.) therapies with new subcutaneous (s.c.) dosage forms being subsequently developed to provide an alternative route of administration. As of August 2022, there have been 9 therapeutic proteins which were developed as a new s.c. dosage form after the approval of the corresponding i.v. product. This article provides a systematic review of prior experiences in the i.v. to s.c. switch development programs. We describe what types of clinical studies were conducted to support the i.v. to s.c. switch for these nine therapeutic proteins. Publicly available scientific advice from health authorities is summarized, particularly regarding recommendations on overall development strategy, dose selection, immunogenicity assessment, and indication extrapolation. The clinical data from these i.v. to s.c. development programs demonstrate that: (1) when switching from i.v. dosing to s.c. dosing, trough drug concentration (Ctrough ) from s.c. dosing should not be inferior to i.v. dosing with average drug concentration (Cavg ; equivalent to AUC, area under the curve after correcting for dosing intervals between i.v. and s.c. administration) being matched or non-inferior to i.v. dosing; and (2) with appropriate s.c. dose regimens, treatment with s.c. therapeutic proteins can generally achieve similar efficacy and safety as the corresponding i.v. products, suggesting that the much higher maximum concentration (Cmax ) after i.v. infusion as compared with that from s.c. injection is often not relevant to the treatment effect.

Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma.

In the primary analysis of the phase III COLUMBA study, daratumumab by subcutaneous administration (DARA SC) demonstrated non-inferiority to intravenous administration (DARA IV) for relapsed or refractory multiple myeloma (RRMM). Here, we report the final analysis of efficacy and safety from COLUMBA after a median of 29.3 months follow-up (additional 21.8 months after the primary analysis). In total, 522 patients were randomized (DARA SC, n=263; DARA IV, n=259). With longer follow-up, DARA SC and DARA IV continued to show consistent efficacy and maximum trough daratumumab concentration as compared with the primary analysis. The overall response rate was 43.7% for DARA SC and 39.8% for DARA IV. The maximum mean (standard deviation [SD]) trough concentration (cycle 3, day 1 pre-dose) of serum DARA was 581 (SD, 315) µg/mL for DARA SC and 496 (SD, 231) µg/mL for DARA IV. Median progression-free survival was 5.6 months for DARA SC and 6.1 months for DARA IV; median overall survival was 28.2 months and 25.6 months, respectively. Grade 3/4 treatment-emergent adverse events occurred in 50.8% of patients in the DARA SC group and 52.7% in the DARA IV group; the most common (≥10%) were thrombocytopenia (DARA SC, 14.2%; DARA IV, 13.6%), anemia (13.8%; 15.1%), and neutropenia (13.1%; 7.8%). The safety profile remained consistent with the primary analysis after longer follow-up. In summary, DARA SC and DARA IV continue to demonstrate similar efficacy and safety, with a low rate of infusion-related reactions (12.7% vs. 34.5%, respectively) and shorter administration time (3-5 minutes vs. 3-7 hours) supporting DARA SC as a preferable therapeutic choice. (Clinicaltrials gov. Identifier: NCT03277105.

Population Pharmacokinetics and Exposure-Response Modeling of Daratumumab Subcutaneous Administration in Patients With Light-Chain Amyloidosis.

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.

Characterization of concurrent target suppression by JNJ-61178104, a bispecific antibody against human tumor necrosis factor and interleukin-17A.

Tumor necrosis factor (TNF) and interleukin (IL)-17A are pleiotropic cytokines implicated in the pathogenesis of several autoimmune diseases including rheumatoid arthritis (RA) and psoriatic arthritis (PsA). JNJ-61178104 is a novel human anti-TNF and anti-IL-17A monovalent, bispecific antibody that binds to both human TNF and human IL-17A with high affinities and blocks the binding of TNF and IL-17A to their receptors in vitro. JNJ-61178104 also potently neutralizes TNF and IL-17A-mediated downstream effects in multiple cell-based assays. In vivo, treatment with JNJ-61178104 resulted in dose-dependent inhibition of cellular influx in a human IL-17A/TNF-induced murine lung neutrophilia model and the inhibitory effects of JNJ-61178104 were more potent than the treatment with bivalent parental anti-TNF or anti-IL-17A antibodies. JNJ-61178104 was shown to engage its targets, TNF and IL-17A, in systemic circulation measured as drug/target complex formation in normal cynomolgus monkeys (cyno). Surprisingly, quantitative target engagement assessment suggested lower apparent in vivo target-binding affinities for JNJ-61178104 compared to its bivalent parental antibodies, despite their similar in vitro target-binding affinities. The target engagement profiles of JNJ-61178104 in humans were in general agreement with the predicted profiles based on cyno data, suggesting similar differences in the apparent in vivo target-binding affinities. These findings show that in vivo target engagement of monovalent bispecific antibody does not necessarily recapitulate that of the molar-equivalent dose of its bivalent parental antibody. Our results also offer valuable insights into the understanding of the pharmacokinetics/pharmacodynamics and target engagement of other bispecific biologics against dimeric and/or trimeric soluble targets in vivo.

The first-in-human study of CNTO 7160, an anti-interleukin-33 receptor monoclonal antibody, in healthy subjects and patients with asthma or atopic dermatitis.

AIMS: To assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of CNTO 7160, an anti-interleukin-33 receptor (IL-33R) monoclonal antibody, in healthy subjects and patients with asthma or atopic dermatitis (AD). METHODS: In Part 1 of this Phase I, randomized, double-blind, placebo-controlled study, healthy subjects (n = 68) received single ascending intravenous (IV) CNTO 7160 dose (0.001 to 10 mg/kg) or placebo. In Part 2, patients with mild asthma (n = 24) or mild AD (n = 15) received 3 biweekly IV CNTO 7160 doses (3 or 10 mg/kg) or placebo. RESULTS: CNTO 7160 was generally well tolerated, with 1 serious adverse event of severe cellulitis reported (AD, CNTO 7160, 3 mg/kg). CNTO 7160 exhibited nonlinear PK (0.01-10 mg/kg). Mean clearance decreased with increasing dose (2.43 to 18.03 mL/d/kg). CNTO 7160 PK was similar between healthy subjects and patients with asthma or AD (3 or 10 mg/kg). Free sIL-33R suppression was rapid and dose dependent. Ex vivo inhibition of p38 phosphorylation of basophils was dose-dependent (1-10 mg/kg) and sustained inhibition (≥75%) was observed at higher doses (3 or 10 mg/kg). PK/PD modelling and simulation suggests that 1 mg/kg IV every 2 weeks provides adequate systemic drug exposure for sustained inhibition of p38 phosphorylation of basophils. Despite confirmation of target engagement, no apparent CNTO 7160 clinical activity was observed in patients (asthma or AD). CONCLUSION: This first-in-human study provides PK, PD and safety data, supporting further clinical investigation of CNTO 7160 in patients with asthma and AD.

Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM): Clinical and Population Pharmacokinetic Analyses.

INTRODUCTION: Daratumumab, a human immunoglobulin Gκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for multiple myeloma. In clinical studies, the median durations of the first, second, and subsequent intravenous infusions of daratumumab were 7.0, 4.3, and 3.4 h, respectively. Splitting the first intravenous infusion of daratumumab over 2 days is an approved alternative dosing regimen to reduce the duration of the first infusion and provide flexibility for patients and healthcare providers. METHODS: The feasibility of splitting the first 16-mg/kg infusion into two separate infusions of 8 mg/kg on Days 1 and 2 of the first treatment cycle was investigated in two cohorts [daratumumab, carfilzomib, and dexamethasone (D-Kd) and daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd)] of the phase 1b MMY1001 study. Additionally, a population pharmacokinetic (PK) analysis and simulations were used to compare the PK profiles of the split first dose regimen with the recommended single first dose regimens of daratumumab in previously approved indications. RESULTS: In MMY1001, following administration of the second half of a split first dose on Cycle 1 Day 2, postinfusion median (range) daratumumab concentrations were similar between split first dose [D-Kd, 254.9 (125.8-435.5) µg/ml; D-KRd, 277.2 (164.0-341.8) µg/ml; combined, 256.8 (125.8-435.5) µg/ml] and single first dose [D-Kd, 319.2 (237.5-394.7) µg/ml]. At the end of weekly dosing, median (range) Cycle 3 Day 1 preinfusion daratumumab concentrations were similar between split first dose [D-Kd, 663.9 (57.7-1110.7) µg/ml; D-KRd, 575.1 (237.9-825.5) µg/ml; combined, 639.2 (57.7-1110.7) µg/ml] and single first dose [D-Kd, 463.2 (355.9-792.9) µg/ml]. The population PK simulations demonstrated virtually identical PK profiles after the first day of treatment for all approved indications and recommended dosing schedules of daratumumab. CONCLUSION: These data support the use of an alternative split first dose regimen of intravenous daratumumab for the treatment of MM. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01998971.

Galeterone and The Next Generation Galeterone Analogs, VNPP414 and VNPP433-3ß Exert Potent Therapeutic Effects in Castration-/Drug-Resistant Prostate Cancer Preclinical Models In Vitro and In Vivo.

These studies compared the efficacies of our clinical agent galeterone (Gal) and the FDA-approved prostate cancer drug, enzalutamide (ENZ) with two lead next generation galeterone analogs (NGGAs), VNPP414 and VNPP433-3ß, using prostate cancer (PC) in vitro and in vivo models. Antitumor activities of orally administered agents were also assessed in CWR22Rv1 tumor-bearing mice. We demonstrated that Gal and NGGAs degraded AR/AR-V7 and Mnk1/2; blocked cell cycle progression and proliferation of human PC cells; induced apoptosis; inhibited cell migration, invasion, and putative stem cell markers; and reversed the expression of epithelial-to-mesenchymal transition (EMT). In addition, Gal/NGGAs (alone or in combination) also inhibited the growth of ENZ-, docetaxel-, and mitoxantrone-resistant human PC cell lines. The NGGAs exhibited improved pharmacokinetic profiles over Gal in mice. Importantly, in vivo testing showed that VNPP433-3ß (at 7.53-fold lower equimolar dose than Gal) markedly suppressed (84% vs. Gal, 47%; p < 0.01) the growth of castration-resistant PC (CRPC) CWR22Rv1 xenograft tumors, with no apparent host toxicity. ENZ was ineffective in this CRPC xenograft model. In summary, our findings show that targeting AR/AR-V7 and Mnk1/2 for degradation represents an effective therapeutic strategy for PC/CRPC treatment and supports further development of VNPP433-3ß towards clinical investigation.

Pharmacokinetics, Pharmacodynamics, Immunogenicity, Safety, and Tolerability of JNJ-61178104, a Novel Tumor Necrosis Factor-Alpha and Interleukin-17A Bispecific Antibody, in Healthy Subjects.

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.

A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate.

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.

Modification of the Fc Region of a Human Anti-oncostatin M Monoclonal Antibody for Higher Affinity to FcRn Receptor and Extension of Half-life in Cynomolgus Monkeys.

The purpose of this study was to evaluate the pharmacokinetics (PK) of anti-oncostatin M (OSM) IgG1 monoclonal antibodies, CNTO 1119 and its Fc variant (CNTO 8212), which incorporates the LS(Xtend) mutation to extend terminal half-life (T1/2 ), after a single intravenous (IV) or subcutaneous (SC) administration in cynomolgus monkeys, and to predict human PK. In study 1, single doses of CNTO 1119 and CNTO 8212 were administered IV or SC at 3 mg/kg to cynomolgus monkeys (n = 3 per group). In study 2, single doses of CNTO 8212 were administered IV at 1, 5 or 20 mg/kg, or SC at 5 mg/kg to cynomolgus monkeys (n = 5 per group). Serial blood samples were collected for assessment of serum concentrations of CNTO 1119 and/or CNTO 8212. A two-compartment population PK model with first-order elimination was utilized to simultaneously describe the serum concentrations of CNTO 1119 and CNTO 8212 over time after IV and SC administration in cynomolgus monkeys. The typical population PK parameter estimates for CNTO 1119 in cynomolgus monkeys were clearance (CL) = 2.81 mL/day/kg, volume of distribution of central compartment (V1 ) = 31.3 mL/kg, volume of distribution of peripheral compartment (V2 ) = 23.3 mL/kg, absolute bioavailability (F) = 0.84 and T1/2 = 13.4 days. In comparison, the typical population PK parameter estimates for CNTO 8212 in cynomolgus monkeys were CL = 1.41 mL/day/kg, V1 = 39.8 mL/kg, V2 = 32.6 mL/kg, F = 0.75 and T1/2 = 35.7 days. The mean CL of CNTO 8212 was ~50% lower compared with that for CNTO 1119 in cynomolgus monkeys. The overall volume of distribution (V1 +V2 ) for CNTO 8212 was about 32% larger compared with that for CNTO 1119, but generally similar to the vascular volume in cynomolgus monkeys. The T1/2 of CNTO 8212 was significantly (p < 0.05) longer by about 2.7-fold than that for CNTO 1119 in cynomolgus monkeys. Thus, the modification of the Fc portion of an anti-OSM IgG1 mAb for higher FcRn binding affinity resulted in lower systemic clearance and a longer terminal half-life in cynomolgus monkeys. CNTO 8212 demonstrated linear PK after a single IV dose (1-20 mg/kg) in cynomolgus monkeys. The predicted human PK parameters suggest that CNTO 8212 is likely to exhibit slow clearance and long terminal half-life in human beings and may likely allow less frequent dosing in the clinical setting.

Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: A proof-of-concept study.

UNLABELLED: The interleukin (IL)-12 signaling cascade has been associated with primary biliary cholangitis (PBC). This multicenter, open-label, proof-of-concept study evaluated the anti-IL12/23 monoclonal antibody, ustekinumab (90 mg subcutaneous at weeks 0 and 4, then every 8 weeks through week 20), in adults with PBC and an inadequate response to ursodeoxycholic acid therapy (i.e., alkaline phosphatase [ALP] >1.67× upper limit of normal [ULN] after ≥6 months). ALP response was defined as a >40% decrease from baseline and ALP remission as ALP normalization (if baseline ALP 1.67×-2.8× ULN) or <1.67× ULN (if baseline ALP >2.8× ULN). Changes in Enhanced Liver Fibrosis (ELF) scores and serum bile acids were also assessed. At baseline, patients had median disease duration of 3.2 years, median ELF score of 9.8, and highly elevated total bile acid concentration (median, 43.3 µmol/L); 13 of 20 (65%) patients had baseline ALP >3× ULN. Although steady-state serum ustekinumab concentrations were reached by week 12, no patient achieved ALP response or remission. Median percent ALP reduction from baseline to week 28 was 12.1%. ELF score decreased slightly from baseline to week 28 (median reduction: 0.173), and total serum bile acid concentrations decreased from baseline to week 28 (median reduction: 8.8 µmol/L). No serious infections or discontinuations resulting from adverse events were reported through week 28. One patient had a serious upper gastrointestinal hemorrhage considered unrelated to test agent by the investigator. CONCLUSION: Open-label ustekinumab therapy, though associated with a modest decrease in ALP after 28 weeks of therapy, did not otherwise appreciably change ALP and overt proof-of-concept was not established as per prespecified primary endpoint of proposed efficacy. No new ustekinumab safety signals were observed. (Hepatology 2016;64:189-199).

Pharmacokinetics and Safety of Single Intravenous Doses of JNJ-54452840, an Anti-ß1-Adrenergic Receptor Antibody Cyclopeptide, in Healthy Male Japanese and Caucasian Participants.

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-ß1-adrenergic receptor (anti-ß1-AR) antibodies, which stimulate the cardiac ß1-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-ß1-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.

CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab.

The objective of this study was to determine the safety and efficacy of carlumab in the treatment of idiopathic pulmonary fibrosis (IPF).A phase 2, randomised, double-blind placebo-controlled dose-ranging study was conducted in patients with IPF (n=126). Patients were randomised to carlumab (1 mg·kg(-1), 5 mg·kg(-1), or 15 mg·kg(-1)) or placebo every 4 weeks. The primary endpoint was the rate of percentage change in forced vital capacity (FVC). Secondary endpoints were time to disease progression, absolute change in FVC, relative change in diffusing capacity of the lung for carbon monoxide (DLCO), and St George's Respiratory Questionnaire (SGRQ) total score.Due to a pre-planned, unfavourable interim benefit-risk analysis, dosing was suspended. The rate of percentage change in FVC showed no treatment effect (placebo -0.582%, 1 mg·kg(-1) -0.533%, 5 mg·kg(-1) -0.799% and 15 mg·kg(-1) -0.470%; p=0.261). All active treatment groups showed a greater decline in FVC (1 mg·kg(-1) -290 mL, 5 mg·kg(-1) -370 mL and 15 mg·kg(-1) -320 mL) compared with placebo (-130 mL). No effect on disease progression, DLCO, infection rates or mortality was observed. SGRQ scores showed a nonsignificant trend toward worsening with active treatment. Unexpectedly, free CC-chemokine ligand 2 levels were elevated above baseline at both 24 and 52 weeks. A higher proportion of patients with one or more serious adverse events was observed in the 5 mg·kg(-1) group (53.1%) compared with 1 mg·kg(-1) (15.2%), 15 mg·kg(-1) (21.9%) and placebo (46.4%), although no unexpected serious adverse events were noted.Although dosing was stopped prematurely, it is unlikely that carlumab provides benefit to IPF patients.

Unexpected Toxicology Findings in Rats Dosed With an Antihuman IL-13 Monoclonal Antibody.

Interleukin 13 (IL-13) is a type 2 helper T cytokine involved in allergic inflammation and immune responses to parasites. CNTO5825 is an antihuman IL-13 monoclonal antibody that inhibits the pharmacological activity of human, cynomolgus monkey, and rat IL-13. Repeated dose toxicology studies of 1- to 6-month duration were conducted in both rats and monkeys at doses of 20 to 100 mg/kg/wk. A decrease in the T cell-dependent antibody response to Keyhole Limpet Hemocyanin immunization was observed in monkeys but not in rats. In the 6-month rat study, there was a 2.2-fold increase in eosinophils in males at 3 and 6 months that was reversible. At necropsy (main and 4-month recovery), rats from control and CNTO5825-dosed groups were found to have pin worms, which may have contributed to the elevations in eosinophil. Testicular toxicity (dilatation of seminiferous tubules, atrophy, and degeneration of the germinal epithelium) was observed in 2 rats at 20 mg/kg and in 5 rats at 100 mg/kg (main and recovery). Brain lesions (unilateral focal accumulation of cells in the white matter of the cerebral cortex) were observed in 2 rats at 100 mg/kg, and vascular neoplasms (1 fatal multicentric hemangiosarcoma and 1 benign hemangioma) were observed at 100 mg/kg/wk. Overall, these studies show that CNTO5825 was without toxicity when administered to rats for up to 6 weeks and to monkeys for up to 6 months. However, when administered to rats for 6 months, a number of seemingly unrelated events occurred that could not be clearly linked to CNTO5825 administration, inhibition of IL-13, or to the immunological status of the animals.

Non-Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics and First-in-Human Dose Selection for CNTO 5825, an Anti-Interleukin-13 Monoclonal Antibody.

CNTO 5825 is a human anti-interleukin-13 (IL-13) monoclonal antibody (mAb) that inhibits binding of human IL-13 to IL-13Rα1 and IL-13Rα2. The purpose of this investigation was to predict human pharmacokinetics (PK) of CNTO 5825 using different allometric approaches and non-clinical PK data in order to select the right and safe doses for first-in-human (FIH) study. After intravenous (IV) administration of CNTO 5825, clearance (CL) ranged from 9.98 to 11.49 ml/day/kg in rats and from 5.78 to 7.19 ml/day/kg in cynomolgus monkeys. The volume of distribution at steady-state (Vss) in rats was large (151.52-155.64 ml/kg) compared to cynomolgus monkey (49.77-61.10 ml/kg). The terminal half-life (T1/2 ) ranged from 12.29 to 14.15 days in rats and from 6.61 to 7.73 days in cynomolgus monkeys. The PK of CNTO 5825 was linear in 1-10 mg/kg dose range in both species. The bioavailability after subcutaneous (SC) administration was 94% and 79% in rats and cynomolgus monkeys, respectively. The predicted CL and Vss based on allometric methods and PK data from rats and monkeys were within twofold of observed CL and Vss in human beings; the predicted CL and Vss in human beings (70 kg) based on time-invariant method with combined PK data from rats and monkeys were 4.84 ± 1.13 ml/day/kg and 68.93 ± 35.55 ml/kg, respectively. The selected doses for the FIH study based on time-invariant method and no observed adverse effect level in toxicity studies in rats and monkeys provided exposures that were subsequently shown to be well tolerated and safe in human beings.

Safety, tolerability and pharmacokinetics of a human anti-interleukin-13 monoclonal antibody (CNTO 5825) in an ascending single-dose first-in-human study.

AIMS: To assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of CNTO 5825 following single-dose intravenous (i.v.) and subcutaneous (s.c.) administration in healthy and healthy atopic subjects. METHODS: Sixty-four subjects received a single dose of placebo or CNTO 5825 (0.1, 0.3, 1.0, 3.0, or 10 mg kg(-1) i.v. in a dose-escalating manner, or 3.0 mg kg(-1) s.c. in healthy subjects; and 10 mg kg(-1) i.v. in healthy atopic subjects). Subjects were observed for 96 h postadministration and followed for 16 weeks. Safety and tolerability were monitored, and serum samples were collected to measure CNTO 5825 concentrations, antibodies to CNTO 5825 and PD biomarkers. RESULTS: Most adverse events were mild to moderate in severity and considered to be unrelated to CNTO 5825, with no dose-dependent trends seen. The two serious adverse events were considered to be unrelated to CNTO 5825. After i.v. administration, CNTO 5825 exhibited linear PK, with a terminal half-life of ∼22-32 days. After a single 3 mg kg(-1) s.c. dose in healthy subjects, CNTO 5825 was absorbed into the systemic circulation with a median time to maximum serum concentration (tmax) of 5.45 days and absolute bioavailability of ∼75%. The PK profile of CNTO 5825 at 10 mg kg(-1) was similar in both healthy and healthy atopic subjects. No antibodies to CNTO 5825 were detected through week 16. In the CNTO 5825-treated healthy atopic subjects, there was a significant reduction in serum IgE and C-C motif chemokine ligand 17 (P = 0.028 and 0.068 vs. placebo, respectively). CONCLUSIONS: CNTO 5825 was well tolerated, had an acceptable safety profile, exhibited linear PK characteristics, and no detected antibodies to CNTO 5825.