This phase 2a, randomised, double-blind, multicentre, placebo-controlled, parallel-group study was done at nine sites across the USA, Poland, and Germany. Patients aged 18 years or older with
rheumatoid arthritis per American College of Rheumatology-European League Against
Rheumatism 2010 criteria and receiving stable
methotrexate were randomly assigned (3:1) by an interactive response technology system to either subcutaneous
otilimab 180 mg or placebo once weekly for 5 weeks, then every other week until week 10 (within a 12-week treatment period), followed by a 10-week safety follow-up. Randomisation was stratified by early
rheumatoid arthritis (≤2 years since diagnosis) and established
rheumatoid arthritis (>2 years since diagnosis). Patients and study personnel (except for an unblinded coordinator or nurse who prepared and administered the study drug) were blinded to treatment assignment; the syringe was shielded during administration. Patients were enrolled by study investigators and allocated to a treatment by central randomisation on the basis of a schedule generated by the sponsor. The primary endpoint was change over time (assessed at baseline and weeks 1, 2, 4, 6, 8, 12, and 22 of follow-up) in 112
biomarkers, including target engagement
biomarkers and those that may be indicative of
rheumatoid arthritis disease activity and response to
otilimab. Secondary endpoints were change from baseline in
synovitis,
osteitis and erosion assessed by
rheumatoid arthritis MRI scoring system (RAMRIS) and
rheumatoid arthritis MRI quantitative score (RAMRIQ), and safety evaluation. The primary, secondary, and safety endpoints were assessed in the intention-to-treat population.
Biomarker and MRI endpoints were analysed for differences between treatment groups using a repeated measures model. This study is registered with ClinicalTrials.gov, NCT02799472.
FINDINGS: Between Aug 9, 2016, and Oct 30, 2017, 39 patients were randomly assigned and included in the analysis (
otilimab n=28; placebo n=11). In the
otilimab group, mean serum concentrations of
GM-CSF-
otilimab complex peaked at week 4 (138·4 ng/L, 95% CI 90·0-212·9) but decreased from week 6-12. CCL17 concentrations decreased from baseline to week 1, remained stable to week 8, and returned to baseline at week 12; least-squares mean ratio to baseline was 0·65 (95% CI 0·49-0·86; coefficient of variation 13·60) at week 2, 0·68 (0·53-0·88; 12·51) at week 4, 0·78 (0·60-1·00; 12·48) at week 6, and 0·68 (0·54-0·85; 11·21) at week 8. No meaningful change in CCL17 concentrations was observed with placebo. In the
otilimab group, the least-squares mean ratio to baseline in
MMP-degraded
type I collagen was 0·86-0·91 over weeks 1-8, returning to baseline at week 12; concentrations remained above baseline at all timepoints in the placebo group. There were no observable differences between
otilimab and placebo for all other
biomarkers. At week 12, least-squares mean change in RAMRIS
synovitis score from baseline was -1·3 (standard error [SE] 0·6) in the
otilimab group and 0·8 (1·2) with placebo; RAMRIQ
synovitis score showed a least-squares mean change from baseline of -1417·0 μl (671·5) in the
otilimab group and -912·3 μl (1405·8) with placebo. Compared with placebo,
otilimab did not show significant reductions from baseline to week 12 in RAMRIS
synovitis,
osteitis and bone erosion, or in RAMRIQ
synovitis and erosion damage. Adverse events were reported in 11 (39%) of 28
otilimab-treated and four (36%) of 11 placebo-treated patients, most commonly
cough in the
otilimab group (2 [7%] of 28; not reported in placebo group), and
pain in extremity (four [36%] of 11) and
rheumatoid arthritis (two [18%] of 11) in the placebo group (not reported in
otilimab group). There were no serious adverse events or deaths.
INTERPRETATION: Serum concentrations of
GM-CSF-
otilimab complex indicated that target engagement was achieved with initial weekly dosing, but not sustained with every other week dosing. CCL17 might be a pharmacodynamic
biomarker for
otilimab activity in future studies.
Otilimab was well tolerated and, despite suboptimal exposure, showed some evidence for improved
synovitis over 12 weeks in patients with active
rheumatoid arthritis.
FUNDING: GlaxoSmithKline.