New post hoc analyses of Phase 3b data examine treatment with Orencia plus methotrexate in patients with early moderate to severe rheumatoid arthritis

Bristol-Myers Squibb Company has announced that data from the OrenciaPhase 3b 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 arthritisTreatment) found that in patients taking Orencia 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 suggestOrencia 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, M.D., 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 3b 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 ofOrencia 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 on Orencia 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 from Orencia 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 3b 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.

About the AVERT Trial

AVERT is a Phase 3b, active-controlled study including 351 adult patients with symptoms of moderate to severe RA for less than two years, positive for ACPA, DAS28 CRP >3.2, and naïve to treatment with MTX and biologic therapies for RA. The patients were randomly assigned to 12 months of weekly treatment in one of three groups:Orencia 125 mg subcutaneous plus MTX; Orencia 125 mg subcutaneous alone; or MTX alone. Participants who had a DAS28 CRP <3.2 (indicating low disease activity) after the 12-month treatment phase were able to continue in a withdrawal period up to 12 months, where all RA treatment including Orencia, MTX and steroids were withdrawn. The co-primary endpoints compared the proportion of patients with DAS28 CRP <2.6 (defined as disease remission in the trial) at month 12 and both months 12 and 18 for combination therapy versus MTX alone. Results demonstrated Orencia plus MTX achieved significantly higher rates of DAS-defined remission at 12 months than treatment with MTX alone (60.9% vs. 45.2%, respectively, p=0.010). Similar results at 12 months were seen with more stringent measures of efficacy including Boolean remission (37.0%, Orencia plus MTX; 22.4%, MTX alone), CDAI remission (42%,Orencia plus MTX; 27.6% MTX alone), and SDAI remission (42%, Orencia plus MTX; 25% MTX alone). Greater benefits on MRI endpoints were also observed with combination therapy vs. MTX alone, including improvements in synovitis and osteitis, and less progression of joint erosions. Specifically at 12 months, mean change from baseline in radiographic non-progression rates as assessed using the RAMRIS method for the synovitis score (-2.35, -1.4 and -0.68, respectively), osteitis score (-2.58, -1.36 and -0.68, respectively) and erosion score (0.19, 1.47 and 1.52, respectively) were observed for the Orencia with MTX, Orencia monotherapy and MTX groups, respectively. Serious adverse events, serious infection events and discontinuation due to serious adverse events were comparable to patients treated with MTX. Rates of serious adverse events were 6.7% and 7.8%, overall infections were 57.1% and 59.5%, serious infections were 0.8% and 0%, malignancies were 0.8% and 0.9%, and autoimmune events were 0.8% and 2.6% for the Orencia combination and MTX groups, respectively.

About the AMPLE Trial

AMPLE is a Phase 3b, randomized, investigator-blinded, multinational study of 24 months duration with a 12-month efficacy primary endpoint (non-inferiority for ACR20). The study included 646 adult biologic-naïve patients with active moderate to severe RA and inadequate response to MTX; 318 in the Orencia plus MTX group and 328 in the adalimumab plus MTX group. Patients were stratified by disease activity and randomized to either 125 mg Orencia SC weekly or 40 mg adalimumab every other week, both on background MTX. The primary endpoint was to determine non-inferiority of Orencia plus MTX to adalimumab plus MTX based on ACR20 response at 12 months. Secondary endpoints included injection site reactions, radiographic non-progression as assessed using the van der Heijde modified total Sharp score (mTSS) method, safety and retention. The complete year-one study results were published in the January 2013 volume of Arthritis & Rheumatism, the official monthly journal of the American College of Rheumatology. Year 2 data were consistent with Year 1. Radiographic progression was also assessed at two years with 85% of patients on the Orenciaregimen and 84% of patients on the adalimumab regimen achieving radiographic non-progression. At 24 months, overall safety data were similar for both groups, including frequency of adverse events (92.8% and 91.5%), serious adverse events (13.8% and 16.5%), and malignancies (2.2% and 2.1%) for the Orencia regimen and the adalimumab regimen, respectively.