Anti-GM-CSF otilimab versus sarilumab or placebo in patients with rheumatoid arthritis and inadequate response to targeted therapies: a phase III randomised trial (contRAst 3)

Abstract

Objectives: To investigate the efficacy and safety of otilimab, an anti-granulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis and an inadequate response to conventional synthetic (cs) and biologic disease-modifying antirheumatic drugs (DMARDs) and/or Janus kinase inhibitors.

Methods: ContRAst 3 was a 24-week, phase III, multicentre, randomised controlled trial. Patients received subcutaneous otilimab (90/150 mg once weekly), subcutaneous sarilumab (200 mg every 2 weeks) or placebo for 12 weeks, in addition to csDMARDs. Patients receiving placebo were switched to active interventions at week 12 and treatment continued to week 24. The primary end point was the proportion of patients achieving an American College of Rheumatology ≥20% response (ACR20) at week 12.

Results: Overall, 549 patients received treatment. At week 12, there was no significant difference in the proportion of ACR20 responders with otilimab 90 mg and 150 mg versus placebo (45% (p=0.2868) and 51% (p=0.0596) vs 38%, respectively). There were no significant differences in Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, pain Visual Analogue Scale or Functional Assessment of Chronic Illness Therapy-Fatigue scores with otilimab versus placebo at week 12. Sarilumab demonstrated superiority to otilimab in ACR20 response and secondary end points. The incidence of adverse or serious adverse events was similar across treatment groups.

Conclusions: Otilimab demonstrated an acceptable safety profile but failed to achieve the primary end point of ACR20 and improve secondary end points versus placebo or demonstrate non-inferiority to sarilumab in this patient population.

Trial registration number: NCT04134728.

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

Figure 1

Trial design. ACR, American College of Rheumatology; b/csDMARD, biologic/conventional synthetic disease-modifying antirheumatic drug; IL-6, interleukin-6; IL-6Ri, IL-6 receptor inhibitor; IR, inadequate response; JAKi, Janus kinase inhibitor; LTE, long-term extension; Q2W, once every 2 weeks; QW, once weekly; RA, rheumatoid arthritis; SC, subcutaneous; W, week.

Figure 2

Patient disposition. *Only one primary reason for treatment discontinuation permitted. †Due to COVID-19 pandemic (n=1). ‡Only one patient in otilimab 90 mg and 150 mg groups and two patients in sarilumab group discontinued treatment due to COVID-19 pandemic. One patient randomised to otilimab 90 mg did not receive any dose of the trial medication. Period 1 is defined as time from randomisation to week 12, period 2 is defined as time from first dose post-week 12 until date of trial completion/withdrawal/treatment withdrawal plus follow-up, whichever is earlier. FU, follow-up, LTE, long-term extension; W, week.

Figure 3

Proportion of patients achieving ACR20 at (A) weeks 12 and 24 and (B) each assessment visit. Statistical comparison of otilimab versus placebo. P values for all other comparisons are provided in the data tables. ACR, American College of Rheumatology; ns, not significant; PBO, placebo; Q2W, once every 2 weeks; QW, once weekly; SE, standard error.

Figure 4

LS mean CFB in (A) HAQ-DI, (B) CDAI total score, (C) FACIT-Fatigue and (D) pain VAS score, at weeks 12 and 24. CDAI, Clinical Disease Activity Index; CFB, change from baseline; FACIT, Functional Assessment of Chronic Illness Therapy; HAQ-DI, Health Assessment Questionnaire-Disability Index; LS, least squares; PBO, placebo; Q2W, once every 2 weeks; QW, once weekly; SE, standard error; VAS, Visual Analogue Scale.