FRI0038 THE RELATIONSHIP BETWEEN ABATACEPT EXPOSURE AND EFFICACY MEASURES IN EARLY MTX-NAIVE ANTI-CITRULLINATED PROTEIN ANTIBODY-POSITIVE PATIENTS WITH RA DURING THE DE-ESCALATION PERIOD OF A PHASE IIIB STUDY

Abstract

Background:Although EULAR/ACR guidelines suggest tapering biologic treatment for RA following sustained remission in patients (pts), specific de-escalation (DE) regimens are not defined. The Phase IIIb Assessing Very Early Rheumatoid arthritis Treatment (AVERT)-2 trial (NCT02504268) is evaluating SC abatacept (ABA) + MTX versus ABA placebo (PBO) + MTX in Anti-Citrullinated Protein Antibody (ACPA)-positive pts with early (ACR/EULAR 2010 criteria; disease duration ≤6 mths), active RA (SDAI >11). AVERT-2 was designed to investigate achievement of SDAI remission and a clinically meaningful dose DE strategy among pts in sustained remission who completed induction with ABA + MTX. In moderately to severely active RA and JIA patients, a relationship between ABA Cmin and efficacy was observed. Therefore, this analysis in very early RA patients, reports on the pharmacokinetics (PK) and immunogenicity of ABA and the maintenance of remission during the DE period of AVERT-2.Objectives:To assess the relationship between changes in ABA exposure and the maintenance of remission and the effect of immunogenicity on exposure during the DE period of AVERT-2.Methods:Pts received blinded SC ABA (125 mg once wkly [QW]) + MTX or ABA PBO + MTX induction treatment for 56 wks. Pts who completed induction with ABA + MTX and had sustained SDAI remission (≤3.3 at Wks 40 and 52) were re-randomized 1:1:1 to ABA QW + MTX for 48 wks (Arm C), ABA every other wk (EOW) + MTX for 24 wks followed by ABA PBO + MTX for 24 wks (Arm D), or ABA QW + MTX PBO for 48 wks (Arm E) in the DE period. ABA trough (Cmin) and anti-drug antibody (ADA) samples were collected in all subjects during the DE period. Serum ABA concentrations and ADA were measured using a validated enzyme immunoassay method and an electrochemiluminescence assay, respectively. Efficacy endpoints included change from DE Day 1 in SDAI score, HAQ-DI score, Physician’s Global Assessment (PhGA), and tender (TJC) and swollen (SJC) joint counts. The relationship between ABA Cmin and efficacy endpoints were assessed. Additionally, the impact of immunogenicity on ABA Cmin was explored.Results:Mean ABA Cmin values remained stable throughout the DE period for subjects in Arms C and E. ABA Cmin values decreased by ~50% in subjects in Arm D for the first 24 weeks from the start of DE and were ~0 for weeks 24-48 consistent with the change in the frequency of ABA dosing from EOW to ABA withdrawal (Figure 1 top).Figure 1:Mean (SD) ABA Cmin values (top) and Mean Change From Baseline in SDAI (bottom) in Subjects in DE Arm C (ABA QW + MTX), D (ABA EOW + MTX followed by ABA placebo + MTX), and E (ABA QW + MTX placebo)The incidence of immunogenicity appeared to increase upon withdrawal of ABA in Arm D. ADA formation did not appear to affect ABA Cmin, as ABA Cmin remained consistent between pts with and without ADA.Upon withdrawal of ABA in Arm D, there appeared to be an increase in the mean change from baseline (Day 1 of DE) in SDAI over time, which followed a similar time course as the washout of ABA (Figure 1 bottom). Similar results were observed for other efficacy endpoints such as HAQ-DI, PhGA, TJC, and SJC.Conclusion:The PK data in these early onset, MTX-naive, ACPA+ RA pts correlated well with the maintenance of remission in Arms A and E. Tapering of ABA from EOW to MTX only in Arm D results in a corresponding decrease in ABA Cmin, an increase in positive antibody response, and loss of remission.