Long-term safety and efficacy of anti-GM-CSF otilimab in patients with rheumatoid arthritis: long-term extension of three phase 3 randomised trials (contRAst X)

Abstract

Objectives: To investigate the long-term safety and efficacy of otilimab, an antigranulocyte-macrophage colony-stimulating factor monoclonal antibody, for patients with rheumatoid arthritis (RA).

Methods: ContRAst X (NCT04333147) was a phase 3, multicentre, long-term extension trial. Patients with RA aged ≥18 years who completed a qualifying contRAst trial (contRAst 1-3) and who the investigator thought might benefit from long-term otilimab treatment were eligible to enter contRAst X. Patients who received otilimab (90 mg/150 mg) in their qualifying trial maintained the same dose; patients who received tofacitinib or sarilumab were rerandomised 1:1 to either otilimab dose. Patients could continue background conventional synthetic disease-modifying antirheumatic drugs. The primary objective was long-term safety (up to 4 years).

Results: Of the 2916 patients who entered contRAst X, 2915 received otilimab (exposure range: 7-896 days); the majority were withdrawn due to early trial termination. For otilimab 90 mg and 150 mg, the incidence of adverse events (AEs) was 62% (n=902/1456) and 64% (n=931/1459), the incidence of AEs of special interest was 8% (n=120/1456) and 7% (n=95/1459) and the incidence of serious AEs was 8% (n=123/1456) and 8% (n=114/1459), respectively. There were no instances of pulmonary alveolar proteinosis (PAP), active tuberculosis (TB), TB reactivation or serious hypersensitivity reactions. The proportions of clinical disease activity index low disease activity responders remained relatively stable throughout, with no apparent reduction following the switch from tofacitinib/sarilumab to otilimab.

Conclusion: No new safety signals or instances of PAP were associated with long-term (≤2.5 years) treatment with otilimab.

Trial registration number: ClinicalTrials.gov: NCT04333147.

Keywords: Clinical Trial; RHEUMATOLOGY; THERAPEUTICS.

Figure 1. Patient disposition. Figure indicates the number of patients who enrolled in contRAst X from each of the qualifying trials (contRAst 1, contRAst 2 or contRAst 3) and the total number enrolled. Green boxes indicate the treatment arm of the qualifying trial that patients were enrolled on. Blue boxes indicate the safety and intent-to-treat (ITT) populations of contRAst X, stratified by prior treatment in the qualifying trial. *Patients who received otilimab in their qualifying trial were assigned to the same dose in contRAst X. ^†Patients who received an active comparator (tofacitinib or sarilumab) were rerandomised 1:1 to either otilimab dose. ^‡One patient was randomised to the otilimab 150 mg arm but was withdrawn due to a physician decision before receiving any dose, and this patient was excluded from the safety and ITT populations. ^§One death due to septic shock occurred after the safety follow-up visit (starting 64 days and resulting in death 65 days after the last dose) and thus was not considered treatment emergent.

Figure 2. Proportion of patients with CDAI low, moderate and high disease activity with (A) otilimab 90 mg and (B) otilimab 150 mg (posthoc analysis). C1, contRAst 1; C2, contRAst 2; C3, contRAst 3; CDAI, Clinical Disease Activity Index.