A Phase IIb Dose-Ranging Randomised Study of Efficacy, Patient-Reported Outcomes and Safety of the Anti-Granulocyte Macrophage Colony-Stimulating Factor Antibody Otilimab (GSK3196165) in Patients with Rheumatoid Arthritis
Background The human monoclonal antibody otilimab inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF), a key driver in immune-mediated inflammatory conditions. We evaluated the efficacy, safety, and key patient-reported outcomes related to pain of otilimab in patients with active rheumatoid arthritis (RA). Methods This Phase IIb, dose-ranging, multicentre, placebo-controlled study was conducted at 64 sites across 14 countries. Patients aged ≥18 years with RA and receiving stable methotrexate were randomised (1:1:1:1:1:1) to subcutaneous placebo or otilimab 22·5, 45, 90, 135 or 180 mg, plus methotrexate, once weekly for 5 weeks, then every other week until week 50. The randomisation schedule was generated by the sponsor and patients assigned to treatment via interactive response technology. Randomisation was blocked (block size of six) but was not stratified. Investigators, patients, and the sponsor were blinded to treatment. An unblinded administrator prepared and administered the study drug. The primary endpoint was DAS28(CRP) <2·6 at week 24. Patients not in the otilimab 180 mg group, without a good/moderate European League Against Rheumatism response (week 12) or with disease activity score for 28 joints with C-reactive protein (DAS28[CRP]) >3·2 (week 24) escaped to otilimab 180 mg; those who escaped were treated as non-responders in their original randomised group. Safety endpoints were incidence of adverse events (AEs) and serious AEs (SAEs), infections and pulmonary events. Efficacy and safety outcomes were assessed in the intent-to-treat population. The study is complete (ClinicalTrials.gov NCT02504671). Findings Between 23 July 2015 and 29 December 2017, 222 patients were randomised (n=37/group). At weeks 12 and 24, 86/175 (49·1%) and 57/83 (68·7%) escaped to otilimab 180 mg, respectively. At week 24, rates of DAS28(CRP) <2·6 were: 2/37 (5%), 6/37 (16%), 7/37 (19%), 5/37 (14%), and 5/37 (14%) in otilimab 22·5 mg, 45 mg, 90 mg, 135 mg, and 180 mg, respectively; 1/37 (3%) in the placebo group. The largest difference was achieved with otilimab 90 mg (16·2%; odds ratio [OR] 8·39; 95% confidence interval [CI] for OR 0·98, 72·14; p=0·0527). Across otilimab dose groups, AEs were reported pre-escape in 19–24 (51–65%) patients and post escape in 10–17 (40–61%) patients; in the placebo group this was 18/27 (27%) and 22/26 (50%), respectively. The most common AE was nasopharyngitis: pre-escape n=3–9 (8–24%) in otilimab groups, n=1 (1%) in the placebo group; post escape n=1–3 (4–10%) in otilimab groups, n=7 (21%) in the placebo group. Pre-escape SAEs were foot fracture (otilimab 45 mg); arthralgia, myocardial infarction, dizziness (otilimab 90 mg); oesophageal spasm, acute pyelonephritis (otilimab 22·5 mg), uterine leiomyoma (otilimab 135 mg), and dizziness. Post-escape SAEs were ankle fracture (placebo) and RA (otilimab 135 mg). There were no deaths or pulmonary events of clinical concern, and rates of serious infection were low. Interpretation Otilimab plus methotrexate was well tolerated and despite not achieving the primary endpoint of DAS28(CRP) remission there were improvements compared with placebo in disease activity scores. Of particular note, patients reported significant improvement in pain and physical function, supporting further clinical development of otilimab in RA.