Efficacy and safety of abatacept in active primary Sjögren's syndrome: results of a phase III, randomised, placebo-controlled trial

Abstract

Objectives: To evaluate efficacy and safety of abatacept in adults with active primary Sjögren's syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial.

Methods: Eligible patients (moderate-to-severe pSS [2016 ACR/European League Against Rheumatism (EULAR) criteria], EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI] ≥5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125 mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored.

Results: Of 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI -3.2 abatacept vs -3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified.

Conclusions: Abatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity.

Keywords: Sjogren's syndrome; autoimmune diseases; therapeutics.

Figure 1

Adjusted mean changes from baseline in clinical efficacy outcomes over time for (A) total ESSDAI score, (B) total ESSPRI score, (C) SWSF (mITT population), (D) Schirmer’s test, (E) tear break-up time and (F) ocular staining scores. (A–C) The results for day 169 in the table are from the primary analysis and the data in the plot are based on the 1-year analysis. (D–F) The adjusted mean differences from placebo (95% CI) at day 169 in the text boxes are from the primary analysis and the data in the plot are based on the 1-year analysis. Study eye is defined as the eye with the higher total score for ocular surface staining at baseline. If both eyes have the same total score for ocular surface staining at baseline, the eye with the lower Schirmer’s test time (STT) at baseline will be selected. If both eyes have equal STT at baseline, then the eye with the lower tear break-up time will be selected. If all of the parameters above are equal, then the right eye will be selected as the study eye. CFB, change from baseline; ESSDAI, EULAR Sjögren’s Syndrome Disease Activity Index; ESSPRI, EULAR Sjögren’s Syndrome Patient Reported Index; mITT, modified intent to treat; NA, not applicable; SWSF, stimulated whole salivary flow.

Figure 2

Adjusted mean change from baseline over time for selected biomarkers to day 365: (A) IgG, (B) IgA, (C) IgM-RF, (D) kappa light chain, (E) C4 complement and (F) CXCL13. P values were nominal. Adjusted mean differences at day 365 are versus the placebo arm switched to abatacept (rather than vs placebo). Biomarker assessments up to 56 days post-dose are included. Estimates of adjusted mean change are from a repeated measure mixed model that includes baseline biomarker result, treatment group, randomisation stratification factors (baseline oral corticosteroid use [yes/no], baseline hydroxychloroquine use [yes/no]), time, time-by-treatment group interaction and time-by-baseline biomarker result interaction. Baseline values were based on those patients included at day 29 (day 85 for CXCL13). *Units are calibrated against standard curves derived from a WHO international reference. CXCL13, chemokine ligand 13; RF, rheumatoid factor.

Figure 3

Adjusted mean change over time from baseline to day 365 in circulating T-cell subtypes: (A) CD4 TEM, (B) Th1, (C) Treg, (D) Tfh and (E) ICOS⁺ Tfh cells. Adjusted mean differences at day 365 are versus the placebo arm switched to abatacept (rather than vs placebo). (A) CD4+TEM expressed as a percentage of CD4+ cells. Markers for CD4 TEM cells=CD3+CD4+CD45RA–CCR7–. (B) Markers for Th1 cells=CD3+CD4+CXCR3+CCR6–. (C) Treg expressed as a percentage of CD4 T cells. Markers for Treg cells=CD3+CD4+CD25+CD127–/LO. (D) Tfh is expressed as a percentage of CD4 +T cells (CXCR5+PD1+). Markers for Tfh cells=CD3+CD4+CD185+CD279+. (E) ICOS⁺ Tfh expressed as a percentage of Tfh cells. Markers for ICOS⁺ Tfh cells=CD3+CD4+CD185+CD279+CD278+. ICOS⁺ Tfh, ICOS-positive Tfh costimulator; TEM, effector memory T cells; Tfh, T follicular helper cells; Th1, T helper type 1 cells; Treg, regulatory T cells.