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

ObjectivesTo investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis.MethodsTwo 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.ResultsThe 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.ConclusionsAlthough 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 numbersNCT03980483,NCT03970837.

Lessons from negative phase 3 trials in rheumatoid arthritis anno 2023

“…René Westhovens , 1 Patrick Verschueren 2 A recent phase 3 trial (contRAst 3) with otilimab, a drug targeting granulocytemacrophage colony-stimulating factor (GM-CSF), was reported by Taylor et al to be negative in a population of patients with rheumatoid arthritis (RA) refractory to conventional synthetic(cs)DMARDs and advanced therapies, including biological(b) DMARDs and targeted synthetic(ts) DMARDs. 1 The trial not only failed to meet its primary endpoint with a weekly subcutaneous (SC) dose of 150 mg otilimab compared with placebo on top of csDMARDs, but also did not demonstrate non-inferiority to the active comparator sarilumab.…”

“…Two other phase 3 trials comparing otilimab with placebo or tofacitinib in patients with an inadequate response to csDMARDs or bDMARDs (contRAst 1 and contRAst 2) showed statistical benefit over placebo but less than tofacitinib. 2 Otilimab was the first drug with this mode of action (MOA) making it to phase 3, based on promising preclinical data confirming the rationale of targeting GM-CSF in RA and on phase 2 trial results. 3 4 Another promising compound targeting GM-CSF, mavrilimumab was not pursued to phase 3, after a phase 2 trial with 100 mg SC every other week versus golimumab 50 mg SC every 4 weeks on top of methotrexate (MTX).…”

Positive and Negative Effects of Administering a Magnetic Field to Patients with Rheumatoid Arthritis (RA)

“…Biological drugs and targeted therapies applied today are very helpful and improve patients’ quality of life [ 21 , 22 , 23 , 24 ]. Some patients, however, are not eligible for such treatment, or they do not respond well to these types of treatment and experience pain and impairments affecting the function of the upper limb [ 25 ].Our study proposed an alternative treatment method that can potentially be administered to patients who do not respond to biological treatments and other pharmacotherapy.This could also be an option for patients referred to rehabilitation treatments and are unable to systematically use outpatient physical therapy. In such cases, a practical solution would involve the self-administration of static magnetic fields emitted by permanent magnets to be used in home settings.…”