Population Pharmacokinetics of the TNF‐α and IL‐17A Dual‐Variable Domain Antibody ABT‐122 in Healthy Volunteers and Subjects With Psoriatic or Rheumatoid Arthritis: Analysis of Phase 1 and 2 Clinical Trials

Abstract

ABT-122 is an IgG1 dual-variable domain immunoglobulin that specifically blocks TNF-α and IL-17A. This work characterized ABT-122 pharmacokinetics using nonlinear mixed-effects modeling and ABT-122 serum concentrations from 72 healthy subjects, 196 subjects with rheumatoid arthritis (RA), and 144 subjects with psoriatic arthritis (PsA) enrolled in 4 phase 1 and 2 phase 2 studies (0.1-10 mg/kg intravenously and 0.3-3 mg/kg subcutaneous single doses and 0.3-3.0 mg/kg subcutaneous and 60-240 mg subcutaneous doses weekly or every other week). A 2-compartment model with a combination of linear clearance (0.419 L/day) and nonlinear clearance (relevant only at low doses; V and K of 0.155 mg/day and 0.0458 mg/L, respectively) described ABT-122 pharmacokinetics. Subcutaneous bioavailability was 35%-58% across formulations and populations. Body weight was a significant covariate for ABT-122 clearance, with subjects with body weight of 140 and 40 kg estimated to have 38% lower and 43% higher ABT-122 AUC, respectively, compared with a 70-kg reference subject. ABT-122 antidrug antibody (ADA) titer (ADA incidence, 47%; 0 to 519 000 titer range in the data set) was a continuous covariate on ABT-122 clearance. An ADA titer of 100 units resulted in a 5-fold increase in clearance. Sex, age, and baseline serum albumin or baseline C-reactive protein level did not impact ABT-122 exposure. Fixed-effects and random-effects parameters were estimated with a relative standard error of ≤17% and ≤28%, respectively, and the model was qualified using bootstrap analysis and visual predictive checks. This analysis characterized ABT-122 exposure across populations and supported exposure-response analyses of ABT-122 efficacy in RA and PsA.

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

“…37 The PK properties of JNJ-61178104 following SC administration were consistent with those of COVA322 and ABT-122 in phase 1 studies, and similar to typical mAbs administered by the SC route. 25,34,35 Additionally, the bioavailability and t max values of the JNJ-61178104 parental compounds were comparable to these observations at similar dose levels in normal healthy volunteers.…”

“…However, it has been suggested that having antigen-binding sites toward TNFα and IL-17A together may contribute to acceleration of clearance of these compound. 25,34,35 The half-life of JNJ-61178104 (4.3-9.7 days) was notably short when compared to its parental mAbs, JNJ-54160444 and golimumab, which were approximately 14.6 (±3.19) days and 12.23 (±2.90) days, respectively, following 1 mg/kg single doses in normal healthy volunteers. Relatively short half-lives have been previously reported for other bispecific antibodies that target TNFα and IL-17A, including COVA-322 and ABT-122 bispecific compounds following single IV doses.…”

“…Relatively short half-lives have been previously reported for other bispecific antibodies that target TNFα and IL-17A, including COVA-322 and ABT-122 bispecific compounds following single IV doses. 25,34,35 The PopPK approach was used to simultaneously describe JNJ-61178104 serum concentrations over time after IV and SC administrations in healthy subjects and to characterize the effect of body weight and ADAs on the PK of JNJ-61178104. Estimates of the PopPK parameters agreed with the NCA results and showed that a 2-compartment linear model with first-order elimination adequately characterized the PK profile of JNJ-61178104 following IV and SC administration in healthy subjects.…”

Phase II Study of ABT‐122, a Tumor Necrosis Factor– and Interleukin‐17A–Targeted Dual Variable Domain Immunoglobulin, in Patients With Psoriatic Arthritis With an Inadequate Response to Methotrexate

“…The proportion of subjects with C trough concentrations below the limit of quantitation at the 12-week time point was~3% in both the ABT-122 120 mg every week and ABT-122 240 mg every week groups. Details of ABT-122 pharmacokinetic results are reported elsewhere (42).…”

Pharmacokinetics, Safety, and Tolerability of the Dual Inhibitor of Tumor Necrosis Factor‐α and Interleukin 17A, ABBV‐257, in Healthy Volunteers and Patients With Rheumatoid Arthritis

“…The rest of the amino acid sequences, the disulfide linkages, and the glycosylation patterns are similar to those of naturally occurring immunoglobulin G1 (IgG1) antibodies. A DVD‐Ig that binds and inhibits human TNF‐α and IL‐17A (ABT‐122) was developed, exhibited target engagement, and demonstrated efficacy in RA and psoriatic arthritis . However, ABT‐122 has shown faster clearance (14.4–30.9 mL/h for intravenous administration; apparent serum clearance [CL/F], 34.0–49.9 mL/h for subcutaneous administration), and a relatively higher incidence of antidrug antibodies (ADAs, 19%–99% in healthy subjects or adult patients with RA or psoriatic arthritis) than has been shown for other IgG1 monoclonal antibodies such as adalimumab (clearance, 12–17 mL/h for intravenous administration; CL/F, 28 mL/h for subcutaneous administration; and ADA incidence, 3%–10% in adult patients with RA, psoriasis, psoriatic arthritis, or hidradenitis suppurativa) .…”