Data from Pharmawand - Curated by EPG Health - Date added 08 November 2019

Bristol-Myers Squibb Company announced new data from the randomized Phase IIIb Assessing Very Early Rheumatoid arthritis Treatment (AVERT)-2 trial exploring de-escalation of therapy in early, seropositive rheumatoid arthritis (RA) patients who achieved sustained Simplified Disease Activity Index (SDAI) remission following induction with Orencia (abatacept) and methotrexate (MTX).

The study showed that, across all Orencia treatment arms, patients achieved maintenance of remission and inhibition of structural damage progression at week 48 after de-escalation. These results will be featured in a late-breaking oral presentation at the 2019 American College of Rheumatology and Association of Rheumatology Professionals (ACR/ARP) Annual Meeting, November 8-13, 2019, in Atlanta.

Results to be presented from a second study, CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory CoNditions) , a prospective cohort study of adult patients with RA recruited from the Corrona registry, demonstrate that in a sample of 138 Orencia-treated patients, higher anti-citrullinated protein antibody (ACPA) concentrations at baseline were associated with improvement in patient-reported outcomes (PROs) in adjusted and unadjusted models, Clinical Disease Activity Index (CDAI) score in the adjusted model and CDAI score in the unadjusted model after six months. This association was not observed in a similar sample size of patients treated with other common therapies, TNF inhibitors (TNFi).

AVERT-2 data demonstrate maintenance of remission at 48 weeks following de-escalation in early RA ACPA-positive patients treated with Orencia : In AVERT-2, ACPA-positive patients with early (ACR/EULAR 2010 criteria; disease duration <6 months), active RA (SDAI greater than 11) were randomized 3:2 to blinded subcutaneous (SC) Orencia (125 mg QW) + methotrexate (MTX) or placebo (PBO) + MTX induction treatment for 56 weeks. The SDAI assesses disease activity in RA. Generally, remission is considered achieved if the score is between 0 and 3.3 included.

Patients who completed induction with Orencia + MTX and had sustained SDAI remission (?3.3 at Weeks 40 and 52) were re-randomized 1:1:1 to Orencia QW + MTX for 48 weeks,Orencia every other week (EOW) + MTX for 24 weeks followed by Orencia PBO + MTX for 24 weeks, or Orencia QW + MTX PBO for 48 weeks in the de-escalation (DE) period. Methotrexate and oral corticosteroid doses in the DE period were stable. Patients with sustained SDAI remission who received Orencia PBO + MTX during induction were not re-randomized and continued this treatment in the DE period in a blinded fashion; no comparisons between this arm and the Orencia arms were made. Endpoints were proportion of patients in SDAI remission, adjusted mean change from DE Day 1 in SDAI score, safety to DE Week 48 and radiographic progression at DE Week 48.

Results demonstrated that combination therapy (Orencia QW + MTX) resulted in the best maintenance of remission.

Remission maintenance was observed across the study arms : Orencia QW + MTX regimen : 74% of patients maintained remission at DE week 48. Orencia QW + MTX PBO regimen : after an initial drop in remission rates to 64%, rates stabilized from DE Week 12. Orencia EOW + MTX regimen : after halving the Orencia dose upon entry to the DE period, remission decreased from 88% at DE Week 0 to 74% at DE Week 24, and then further decreased to 48% at DE Week 48 after Orencia was fully withdrawn at DE Week 24. Orencia PBO + MTX regimen : at DE Week 48, 59% of patients who received Orencia PBO + MTX during induction maintained remission with this treatment. Adjusted mean change in SDAI score in the Orencia arms in the DE period was numerically low, but varied between arms and increased (patients’ disease activity worsened) following Orencia withdrawal from the Orencia EOW + MTX arm at DE Week 24. Sustained inhibition of structural damage was seen in all Orencia arms. Safety was similar across treatments with no new signals.

“Although the American College of Rheumatology and European League Against Rheumatism guidelines suggest tapering of biologic therapy following a period of sustained remission in rheumatoid arthritis patients, additional research has been needed to identify appropriate de-escalation regimens for individual therapies,” said Paul Emery, M.D., Director of the Leeds NIHR Biomedical Research Centre, Leeds Teaching Hospitals Trust. “The findings from the AVERT-2 study are important because they reveal the potential for maintenance of clinical remission and inhibition of structural damage with Orencia in early, moderate-to-severe rheumatoid arthritis positive for anti-citrullinated protein antibody, a population that historically has faced a poor prognosis and a more severe disease course, and provide important scientific information related to de-escalation of Orencia therapy.”

Corrona CERTAIN analysis finds greater improvement in PROs and CDAI at six months in Orencia-treated early RA, ACPA-positive patients : Previous Orencia clinical trial research demonstrated that RA patients who test positive for higher ACPA concentrations show a better response to treatment with Orencia than those with lower concentrations. With the Corrona CERTAIN analysis, researchers assessed the association between baseline ACPA concentration and six-month treatment responses to Orencia or TNFis in a real-world setting. The Corrona RA Registry is the largest RA real-world prospective cohort study in the world. The study found significant differences between ACPA quartiles at baseline in mean CDAI, SJC28, CRP, DAS28 (CRP), RF, mHAQ and physician global assessment, and in mean RF, mHAQ and PtGA among TNFi initiators. Among Orencia initiators, but not TNFi initiators, a greater improvement at six months in CDAI and all PROs was observed with increasing ACPA quartile. In the adjusted analysis, among Orencia initiators, there was a numerically greater improvement in CDAI (p=0.208) and statistically significantly greater improvements in all PROs (p<0.05) with increasing ACPA quartile.

“Because rheumatoid arthritis can impact patients in different ways, responses we see in clinical trials do not always translate to routine clinical practice,” said Leslie R. Harrold, M.D., M.P.H., associate professor of medicine, UMass Medical School and chief scientific officer, Corrona, LLC. “The data from this particular sample, showing improvement in CDAI, a measure of disease activity, and patient-reported outcomes in patients positive for anti-citrullinated protein antibody taking Orencia are important for physicians to consider because they replicate, in a real-world setting, what previous clinical research has shown: that this specific treatment may have benefit for this particular patient population.” Safety was not assessed in this observational study.

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