First-In-Human, Phase 1, Randomized, Dose-Escalation Trial with Recombinant Anti-IL-20 Monoclonal Antibody in Patients with Psoriasis

PLoS One. 2015 Aug 7;10(8):e0134703. doi: 10.1371/journal.pone.0134703. eCollection 2015.

Abstract

Background: The current trial was a first-in-human clinical trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the recombinant monoclonal anti-interleukin-20 (IL-20) antibody, NNC0109-0012, which targets the inflammatory cytokine IL-20.

Methods: In total, 48 patients aged 18 to 75 years with moderate to severe stable chronic plaque psoriasis with affected body surface area ≥15% and physician global assessment score ≥3 were enrolled in this randomized, double-blind, multicenter, placebo-controlled, phase 1 dose-escalation trial. Patients were randomized within each single dose cohort (0.01, 0.05, 0.2, 0.6, 1.5, or 3.0 mg/kg) or multiple dose cohort (0.05, 0.2, 0.5, 1.0, or 2.0 mg/kg; 1 dose every other week for 7 weeks) of NNC0109-0012 or placebo in a 3:1 ratio. In the expansion phase, 7 patients were randomized to weekly doses of 2.0 mg/kg NNC0109-0012 or placebo for 7 weeks. The primary objective, safety and tolerability, was assessed by evaluating adverse events (AEs). Additional endpoints included pharmacokinetics, pharmacodynamics, and clinical response (assessed using the Psoriasis Area and Severity Index [PASI] score).

Results: AEs were reported in 85% of patients (n = 40) in the initial study phases (NNC0109-0012, 83%; placebo, 92%) and in 4 of 7 patients in the multiple-dose expansion phase. One serious AE was reported but was judged not to be causally related to NNC0109-0012. No dose-limiting toxicities were reported. NNC0109-0012 pharmacokinetics was similar to other monoclonal antibodies, with an average half-life of approximately 3 weeks. There was a dose-proportional increase in area under the curve and maximum concentration after single dosing. No substantial changes in pharmacodynamic parameters were observed. The expansion phase was terminated early due to apparent lack of PASI improvement.

Conclusion: Single and multiple doses of NNC0109-0012, ranging from 0.05 to 3.0 mg/kg, were well tolerated in patients with psoriasis and exhibited pharmacokinetics similar to that of other monoclonal antibodies.

Trial registration: ClinicalTrials.gov NCT01261767.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing / adverse effects
  • Antibodies, Neutralizing / pharmacology
  • Antibodies, Neutralizing / therapeutic use*
  • Broadly Neutralizing Antibodies
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Interleukins / immunology*
  • Male
  • Middle Aged
  • Psoriasis / drug therapy*
  • Psoriasis / pathology
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / pharmacokinetics
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Treatment Outcome
  • Young Adult

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • Broadly Neutralizing Antibodies
  • Interleukins
  • Recombinant Proteins
  • Fletikumab
  • interleukin 20

Associated data

  • ClinicalTrials.gov/NCT01261767

Grant support

The study was funded by Novo Nordisk A/S, Denmark. Co-authors Mia Sandberg Lundblad (MSL), Marie Göthberg (MG), and Brett E. Skolnick (BES) were employed by Novo Nordisk during the course of the study. Novo Nordisk provided support in the form of salaries for authors MSL, MG, and BES, and was involved in the study design, data collection and analysis, decision to publish, and preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.