A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee

Abstract

Introduction: AMG 108 is a fully human, immunoglobulin subclass G2 (IgG2) monoclonal antibody that binds the human interleukin-1 (IL-1) receptor type 1, inhibiting the activity of IL-1a and IL-1b. In preclinical studies, IL-1 inhibition was shown to be beneficial in models of osteoarthritis (OA). The purpose of this two-part study was to evaluate the safety and pharmacokinetics (PK; Part A) and clinical effect (Part B) of AMG 108 in a double-blind, placebo-controlled, multiple-dose study in patients with OA of the knee.

Methods: In Part A, patients received placebo or AMG 108 subcutaneously (SC; 75 mg or 300 mg) or intravenously (IV; 100 mg or 300 mg) once every 4 weeks for 12 weeks; in Part B, patients received placebo or 300 mg AMG 108 SC, once every 4 weeks for 12 weeks. The clinical effect of AMG 108 was measured in Part B by using the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index pain score.

Results: In Part A, 68 patients were randomized, and 64 received investigational product. In Part B, 160 patients were randomized, and 159 received investigational product. AMG 108 was well tolerated. Most adverse events (AEs), infectious AEs, serious AEs and infections, as well as withdrawals from the study due to AEs occurred at similar rates in both active and placebo groups. One death was reported in an 80-year-old patient (Part A, 300 mg IV AMG 108; due to complications of lobar pneumonia). AMG 108 serum concentration-time profiles exhibited nonlinear PK. The AMG 108 group in Part B had statistically insignificant but numerically greater improvement in pain compared with the placebo group, as shown by the WOMAC pain scores (median change, -63.0 versus -37.0, respectively).

Conclusions: The safety profile of AMG 108 SC and IV was comparable with placebo in patients with OA of the knee. Patients who received AMG 108 showed statistically insignificant but numerically greater improvements in pain; however, minimal, if any, clinical benefit was observed.

Trial registration: This study is registered with ClinicalTrials.gov with the identifier NCT00110942.

Figures

Figure 1

CONSORT diagram. Admin. Decision, administrative decision; AE, adverse event; IV, intravenous; SC, subcutaneous.

Figure 2

Laboratory values over time, Part B. (a) Absolute neutrophil count (ANC); (b) C-reactive protein levels over time.

Figure 3

Pharmacokinetic results: AMG 108 serum concentrations. (a) part a, intravenous administration; (b) part a, subcutaneous administration; (c) part b, subcutaneous administration. IV, intravenous; LLOQ, lower limit of quantification; nM, nanomole; SC, subcutaneous.

Figure 4

Median change from baseline in WOMAC pain scores. (a) Last observation carried forward (LOCF) and observed change from baseline. Note: Primary LOCF analysis at week 6 includes only the evaluable patients randomized to the WOMAC study (one AMG 108 patient was not evaluable); observed analyses at weeks 6 and 12 include all evaluable patients. (b) Change from baseline, by stratification for pain at baseline. dGEMRIC, delayed gadolinium-enhanced magnetic resonance imaging of cartilage; LOCF, last observation carried forward; WOMAC, Western Ontario and McMaster Universities osteoarthritis index pain score.