Nipocalimab, an anti-FcRn monoclonal antibody, in participants with moderate to severe active rheumatoid arthritis and inadequate response or intolerance to anti-TNF therapy: results from the phase 2a IRIS-RA study

Abstract

Objectives: To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent.

Methods: In this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18.

Results: 53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): -1.03 (-1.66 to -0.40) vs -0.58 (-1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement.

Conclusions: Despite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA.

Trial registration number: NCT04991753.

Keywords: Anti-Citrullinated Protein Antibodies; Arthritis, Rheumatoid; Patient Reported Outcome Measures; Rheumatoid Factor.

Figure 1

LS Mean (95% CI) change from baseline in DAS28-CRP at Week 12. ANCOVA, analysis of covariance; DAS28-CRP, Disease Activity Score 28 using C reactive protein; LS Mean, least squares mean; MTX, methotrexate. *The LS Mean difference between nipocalimab and placebo, the CIs and the p values were based on an ANCOVA model adjusted for baseline DAS28-CRP and randomised stratification factor (baseline MTX use).

Figure 2

(A) Number of participants who achieved ACR20, ACR50, ACR70 and ACR90 responses at Week 12, (B) LS Mean (95% CI) change from baseline in HAQ-DI score at Week 12 and (C) LS Mean (95% CI) change from baseline in CDAI score at Week 12. ACR20, ≥20% response in American College of Rheumatology criteria; ACR50, ≥50% response in American College of Rheumatology criteria; ACR70, ≥70% response in American College of Rheumatology criteria; ACR90, ≥90% response in American College of Rheumatology criteria; ANCOVA, analysis of covariance; CDAI, Clinical Disease Activity Index; CMH, Cochran-Mantel-Haenszel; HAQ-DI, Health Assessment Questionnaire-Disability Index; LS Mean, least squares mean; MTX, methotrexate. *The treatment difference between nipocalimab and placebo and the CIs for ACR was based on the Wald statistic with the CMH weight. The treatment difference between nipocalimab and placebo for HAQ-DI and CDAI scores were reported based on LS Means and p values calculated based on the ANCOVA model. †The p value was based on the CMH χ² test, stratified by randomised stratification factor (baseline MTX use). The Mantel-Fleiss criterion was not satisfied with the indicated p values and was therefore based on Fisher’s exact test. The nominal p values presented for secondary and exploratory endpoints are for descriptive purposes only and do not represent statistical significance.

Figure 3

Mean (SD) per cent change from baseline in albumin, LDL and total cholesterol levels (safety population). LDL, low-density lipoprotein cholesterol.

Figure 4

Median (IQR) per cent change from baseline at the trough in PD and disease-related biomarkers*: (A) total IgG, (B) C3d-CIC, and (C) ACPA IgG (anti-CCP2). ACPA, anticitrullinated protein autoantibody; anti-CCP2, anticyclic citrullinated peptide 2 antibody; C3d-CIC, complement factor 3d-containing circulating immune complex; IgG, immunoglobulin G; PD, pharmacodynamic. *The per cent change from baseline at the trough (y-axis) at the indicated visit week (x-axis) was stratified by treatment group for levels of (A) total IgG, (B) C3d-CIC and (C) ACPA IgG (anti-CCP2). If a participant missed a planned dose of study intervention at any visit, their data were excluded from all subsequent visits after the first occurrence of a missed dose. Participants with baseline levels of the indicated analyte below the lower limit of quantitation were excluded.

Figure 5

Median (IQR) per cent change from baseline at trough in ACPA IgG (anti-CCP2) levels versus (A) DAS28-CRP remission and (B) ACR50 response at Week 12.* ACPA, anticitrullinated protein autoantibody; ACR50, ≥50% response in American College of Rheumatology criteria; anti-CCP2, anticyclic citrullinated peptide 2 antibody; DAS28-CRP, Disease Activity Score 28 using C reactive protein; IgG, immunoglobulin G. *Per cent change in anti-CCP2 levels from baseline at Week 12 visit at the trough (y-axis) was stratified by (A) DAS28-CRP remission at Week 12, (B) ACR50 response at Week 12 and treatment group (x-axis). If a participant missed a planned dose of study intervention at any visit, their data were excluded from all subsequent visits after the first occurrence of a missed dose. Participants with baseline anti-CCP2 levels below the lower limit of quantitation were excluded. Data are presented as box (IQR) and whiskers (minimum and maximum values), with the median indicated by a bar.

Figure 6

Associations of baseline ACPA IgG (anti-CCP2) levels and (A) DAS28-CRP remission and (B) ACR50 responses.* ACPA, anticitrullinated protein autoantibody; ACR50, ≥50% response in American College of Rheumatology criteria; anti-CCP2, anticyclic citrullinated peptide 2 antibody; DAS28-CRP, Disease Activity Score 28 using C reactive protein; IgG, immunoglobulin G. *Percentage of participants achieving (A) DAS28-CRP remission or (B) ACR50 response at Week 12 visit (y-axis) was stratified by treatment group and by either all participants or participants with baseline anti-CCP2 levels above the median value (x-axis). Participants with baseline anti-CCP2 levels below the lower limit of quantitation were excluded. The total number of participants in the strata is indicated below the x-axis, and the percentage of participants achieving responses is indicated above the respective bars.