Phase 1b Study of the Safety, Pharmacokinetics, and Disease-related Outcomes of the Matrix Metalloproteinase-9 Inhibitor Andecaliximab in Patients With Rheumatoid Arthritis

Clin Ther. 2018 Jan;40(1):156-165.e5. doi: 10.1016/j.clinthera.2017.11.011. Epub 2017 Dec 26.


Purpose: Andecaliximab (GS-5745) is a highly selective monoclonal antibody against matrix metalloproteinase-9 (MMP9), a proteolytic enzyme implicated in the pathogenesis of rheumatoid arthritis (RA). This study assessed the safety and pharmacokinetic (PK) parameters of andecaliximab in patients with RA and evaluated the effects of andecaliximab treatment on exploratory disease biomarkers.

Methods: In this double-blind, Phase 1b trial, patients with active RA were randomized (4:1) to receive 400-mg andecaliximab or placebo every 2 weeks for a total of 3 intravenous infusions. The primary and secondary end points were safety and the PK parameters of andecaliximab, respectively. Data were summarized by using descriptive statistics.

Findings: A total of 18 patients were randomized; 15 received andecaliximab (participants with confirmed RA diagnosis without current administration of a biologic DMARD a biologic DMARD (disease-modifying antirheumatic drug), aged 18 to 70 years old, weighing >45 to <120 kg). No deaths, serious adverse events, or study discontinuations occurred. All reported adverse events were grade 1 or grade 2 in severity. Mean plasma andecaliximab exposure was 587 d · µg/mL and 878 d · µg/mL at days 1 and 29, respectively, suggesting moderate accumulation. The median terminal t1/2 was 5.65 days; mean volume of distribution at steady state was 4560 mL. Mean MMP9 coverage (the percentage of total plasma MMP9 bound by therapeutic antibody) was maintained at ~80% after the first administration of andecaliximab.

Implications: Andecaliximab administered as 3 infusions over 29 days was generally safe and well tolerated in patients with RA. The majority of total plasma MMP9 was bound by andecaliximab after the first administration. Clinical studies of increased treatment duration in larger patient cohorts are warranted. identifier: NCT02176876. Registered on 25 June 2014.

Keywords: autoimmune diseases; cartilage matrix; matrix metalloproteinase-9; pharmacokinetics; rheumatoid arthritis; therapeutic antibody.

Publication types

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

MeSH terms

  • Aged
  • Antibodies, Monoclonal* / adverse effects
  • Antibodies, Monoclonal* / pharmacokinetics
  • Antibodies, Monoclonal* / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Antirheumatic Agents* / adverse effects
  • Antirheumatic Agents* / pharmacokinetics
  • Antirheumatic Agents* / therapeutic use
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / metabolism
  • Double-Blind Method
  • Female
  • Humans
  • Infusions, Intravenous
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors* / adverse effects
  • Matrix Metalloproteinase Inhibitors* / pharmacokinetics
  • Matrix Metalloproteinase Inhibitors* / therapeutic use
  • Middle Aged


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antirheumatic Agents
  • Matrix Metalloproteinase Inhibitors
  • andecaliximab
  • Matrix Metalloproteinase 9

Associated data