Bristol-Myers Squibb to present data from the Orencia Phase IIIb AVERT and AMPLE trials

Bristol-Myers Squibb Company (NYSE:BMY) announced today data from the Orencia Phase IIIb AVERT and AMPLE trials will be presented in three separate posters during the European League Against Rheumatism Annual Congress (EULAR 2015). These trials included early moderate to severe rheumatoid arthritis (RA) patients with active disease and markers of poor prognosis, such as ACPA (anti-citrullinated protein antibody) and rheumatoid factor (RF), which are both associated with more severe disease progression and joint damage. These data suggest a correlation between ACPA and treatment outcomes, and provide further data regarding the use of Orencia plus methotrexate (MTX) in these RA patients. In RA, activated T-cells in the immune response drive downstream inflammatory events that produce autoantibodies. Inhibiting T-cell activation in the immune response may help reduce autoantibody formation and levels.

One post hoc analysis of AVERT (Assessing Very Early Rheumatoid arthritis Treatment) found that in patients takingOrencia plus MTX, the proportion of patients who maintained DAS-defined remission (DAS<2.6) following drug withdrawal was higher in patients with disease duration of three months or less (33%), compared with patients with longer disease duration (>3 to ≤6 months, 14.7%; >6 months, 10.2%). Shorter disease duration was also associated with a faster onset of clinical response.

Exploratory data from the AVERT study assessed the impact of Orencia plus MTX on different types of ACPA and any association with clinical response. These data suggest Orencia in combination with MTX had greater clinical efficacy in patients who were IgM antibody type ACPA positive at the beginning of the study than in those who were negative for that antibody type, and in those who seroconverted (changed from ACPA positive to negative) over time than those who did not (61.5% vs. 41.2% achieved Boolean remission), suggesting the impact on ACPA is associated with a clinical benefit for RA patients.

“These data are among the first to demonstrate the potential impact of a biologic therapy on ACPA in the early stages of RA, which is characterized by high autoimmune activity and the presence of autoantibodies,” said T.W.J. Huizinga, MD, PhD, Leiden University Medical Center, Leiden Netherlands. “The findings further provide insight into the role of biological response markers in helping define the disease and manage therapy.”

Additionally, an exploratory analysis of AMPLE (Abatacept Versus Adalimumab Comparison in Biologic-Naïve rheumatoid arthritis (RA) Subjects With Background Methotrexate) suggests higher serum ACPA levels at baseline correlated with a better clinical response from Orencia plus MTX compared to adalimumab plus MTX. When patients were divided into quartiles based on baseline ACPA titer, significant differences in response were observed between patients in the highest titer quartile (Q4) versus Q1–3 for DAS28 (CRP) and HAQ-DI (p=0.003 and p=0.021, respectively) in the Orencia treated arm, while, Q4 versus Q1–3 treatment differences were not significant with adalimumab (p=0.358 and p=0.735). 

“These analyses yield promising insights into RA disease progression,” said Douglas Manion, M.D., Head of Specialty Development, Bristol-Myers Squibb. “With further investigation, we can provide additional understanding into the use of Orencia plus methotrexate in patients with early, active, moderate to severe RA.”

New Analyses from the AVERT Trial

The primary results of the AVERT Phase IIIb trial have been previously reported. New data being presented at EULAR 2015 include two analyses exploring the impact of earlier treatment with Orencia and the impact of Orencia on the RA disease process.

AVERT Outcomes By Baseline Disease Duration / June 12, 2015 at 12:05 PM CET: On Drug and Drug-free Remission by Baseline Disease Duration in the AVERT Trial: Abatacept versus Methotrexate Comparison in Patients with Early Rheumatoid Arthritis. VP Bykerk, et al.

The post hoc analysis examined the association of disease duration with the effects of Orencia plus MTX versus MTX treatment on DAS–defined remission (DAS28 [CRP] <2.6) and improvement in physical function (HAQ-DI; ≥0.3 units from baseline). The analysis included the following subgroups: 36 patients on Orencia plus MTX and 48 on MTX with ≤3 months disease duration; 34 patients on Orencia plus MTX and 29 on MTX with >3 to ≤6 months disease duration; 49 patients onOrencia plus MTX and 39 on MTX with >6 months disease duration. The results showed the combination of Orencia and MTX provided greater benefits than MTX alone in patients with a disease duration of ≤3 months: 33% of these patients maintained DAS-defined remission, compared to 14.7% of patients with a disease duration of >3 to ≤6 months and 10.2% with a duration of >6 months. Patients with ≤3 months disease duration also had the fastest onset of clinical response fromOrencia plus MTX; as early as Day 29, 25% of patients treated with Orencia plus MTX with a disease duration of ≤3 months achieved DAS-defined remission, compared with 11.8% of patients with a disease duration of >3 to ≤6 months and 6.1% of patients with a disease duration of >6 months, and 8.3% with MTX alone (≤3 month disease duration). In the MTX arm, 10.4% of patients with a disease duration of ≤3 months maintained DAS-defined remission, compared to 13.8% of patients with a disease duration of >3 to ≤6 months and 5.1% with a duration of >6 months.

AVERT ACPA – Efficacy By Baseline CCP2 Titers and Sero-Conversion Status / June 11, 2015 at 1:45 p.m. CET: Effect of Anti-Cyclic Citrullinated Peptide 2 Immunoglobulin M Serostatus on Efficacy Outcomes Following Treatment with Abatacept Plus Methotrexate in the AVERT Trial. TWJ Huizinga, et al.

This analysis explored the association between patients’ ACPA and ACPA seroconversion status and efficacy outcomes of remission rate at 12 months (remission was assessed using CDAI, SDAI, Boolean, and DAS28 [CRP] <2.6-defined remission) and mean change in DAS28 (CRP) and HAQ-DI over time. A total of 200 out of the 342 patients included in the analysis were baseline anti-CCP2 IgM positive: Orencia plus MTX (n=66), Orencia  monotherapy (n=62) and MTX (n=72). The results showed ACPA-IgM positive patients treated with Orencia plus MTX achieved the greatest mean improvements in DAS28 (CRP) and HAQ-DI over time, as well as remission in all four indices, compared with patients who were ACPA-IgM negative at baseline. In addition, 61.5% of patients in the Orencia plus MTX group who seroconverted (i.e., changed from ACPA-IgM positive at baseline to ACPA-IgM negative at Month 12) achieved the more stringent Boolean remission, compared to 41.2% who remained positive, suggesting an association between remission and the impact on IgM ACPA.

New Analysis from the AMPLE Trial

The primary results of the AMPLE Phase IIIb trial have been previously reported. AMPLE is the first non-inferiority, head-to-head study in adults with RA comparing biologic agents, Orencia and adalimumab, on a background of MTX. New data being presented at EULAR 2015 includes an exploratory analysis examining outcomes in early RA patients stratified by ACPA titer.

Comparison of Patient-Reported Outcomes by Baseline ACPA Category in AMPLE / June 13, 2015 at 10:15 a.m. CET: Effect of Baseline Anti-Cyclic Citrullinated Peptide 2 Antibody Titre on Patient-Reported Outcomes Following Treatment with Subcutaneous Abatacept or Adalimumab. J Sokolove, et al.

This post hoc analysis assessed patient-reported outcomes (PROs) in 388 patients who were grouped into quartiles based on increasing ACPA titers (Q1=28-235 AU/mL; Q2=236-609 AU/mL; Q3=613-1046 AU/mL; Q4=1060-4894 AU/mL). There were 97 patients per quartile. The number of patients per treatment group in each quartile were (abatacept, adalimumab): Q1=42, 55; Q2=51, 46; Q3=46, 51; Q4=46, 51. PROs assessed included pain, quality of life, disability, and physical functioning. The results showed Orencia plus MTX-treated patients with the highest ACPA titers reported greater improvement than those in the lowest ACPA quartiles across measures of pain, physical function and clinical outcomes. These patterns were less pronounced among patients treated with adalimumab.