Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2)

Abstract

Objectives: To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis.

Methods: Two phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints.

Primary endpoint: proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12.

Results: The intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients.

Primary endpoint: proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups.

Conclusions: Although otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib.

Trial registration numbers: NCT03980483, NCT03970837.

Keywords: autoimmune diseases; biological therapy; cytokines; inflammation; rheumatoid arthritis.

Figure 1

ContRAst 1 and 2 study design. *Stable oral dose of MTX and ≥5 mg/week folic acid as standard of care. †Otilimab solution in vial/pre-filled syringe. ‡Tofacitinib administered as 5 mg oral capsule. ACR20, 20% improvement in American College of Rheumatology criteria; b/csDMARD, biologic/conventional synthetic disease-modifying antirheumatic drug; C1, contRAst 1; C2, contRAst 2; IR, inadequate response; JAKi, Janus kinase inhibitor; LTE, long-term extension; MTX, methotrexate; RA, rheumatoid arthritis, SC, subcutaneous; W, week.

Figure 2

Proportion of patients achieving (A) ACR20 and (B) CDAI LDA at weeks 12, 24 and 52, and (C) LS mean CFB in HAQ-DI score at weeks 12, 24 and 52. *Otilimab versus placebo, per SAP. Comparison of tofacitinib versus placebo was not included in the SAP; however, statistical data are provided in the data tables. ACR, American College of Rheumatology; CDAI, Clinical Disease Activity Index; CFB, change from baseline; HAQ-DI, Health Assessment Questionnaire-Disability Index; LDA, low disease activity; LS, least squares; PBO, placebo; SAP, statistical analysis plan.

Figure 3

LS mean CFB in (A) pain VAS, (B) FACIT-Fatigue and (C) CDAI Due to the step-down multiple testing approach, statistical significance was not assessed, or cannot be claimed, for otilimab versus placebo for these endpoints; however, statistical data are provided in the data tables. CDAI, Clinical Disease Activity Index; CFB, change from baseline; FACIT, Functional Assessment of Chronic Illness Therapy; LS, least squares; PBO, placebo; VAS, Visual Analogue Scale.