Long-term safety and efficacy of abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: a 7-year extended study R. Westhovens1,2, J.M. Kremer3, P. Emery4,5, A.S. Russell6, R. Alten7, E. Barré8, M. Dougados9 1Department of Development and Regeneration, Neuro-musculo-skeletal Research Unit, KU Leuven, Belgium; 2Rheumatology, University Hospitals Leuven, Belgium; 3Center for Rheumatology, Albany Medical College, Albany, United States; 4Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom; 5NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals Trust, Leeds, United Kingdom; 6University of Alberta Hospital, Alberta, Canada; 7Schlosspark-Klinik & University Medicine Berlin, Berlin, Germany; 8Bristol-Myers Squibb, Braine-L’Alleud, Belgium; 9Hôpital Cochin, Descartes University, Paris, France. Abstract Objective To assess the safety and efficacy of intravenous (IV) abatacept plus methotrexate (MTX) over 7 years, the longest observational period to date, in patients with established rheumatoid arthritis (RA) and an inadequate response to MTX. Methods Patients randomised to IV abatacept (10 or 2 mg/kg) or placebo, plus MTX, during the 1-year double-blind (DB) period of a Phase 2b study could enter the long-term extension (LTE) and receive IV abatacept 10 mg/kg monthly. Safety was assessed in patients who received ≥1 dose of abatacept; efficacy was assessed in patients originally randomised to 10 mg/kg abatacept (as-observed data). Results A total of 219 patients entered the LTE; 114 (52.1%) completed 7 years of treatment with abatacept plus MTX. Cumulative (DB + LTE) incidence rates of serious adverse events, serious infections, malignancies, and autoimmune events were 17.6, 3.2, 1.8, and 1.2/100 patient-years, respectively. Safety was consistent between the DB (n=220) and cumulative (n=287) periods. Improvements in American College of Rheumatology responses, disease activity, and normalisation of physical function and health-related quality of life were maintained over time. Approximately 80% of patients who achieved low disease activity or normalised modified Health Assessment Questionnaire scores at Year 1, and who remained in the study, sustained these responses in each subsequent year. Conclusion IV abatacept in combination with MTX demonstrated consistent safety and sustained efficacy over 7 years in MTX inadequate responders with established RA. Furthermore, some patients demonstrated a normalisation of physical function and health-related quality of life that was sustained over time. Key words abatacept, rheumatoid arthritis, long-term effects, treatment efficacy, safety. Clinical and Experimental Rheumatology 2014; 32: 553-562. 7-year abatacept plus methotrexate therapy / R. Westhovens et al. Rene Westhovens, MD Introduction date. In accordance with the European Joel M. Kremer, MD The chronic nature of rheumatoid ar- League Against Rheumatism (EULAR) Paul Emery, MD thritis (RA) results in patients receiv- and ACR guidelines, which emphasise Anthony S. Russell, MD ing biologic treatment for long peri- the importance of the sustainability of Rieke Alten, MD Emilie Barré ods of time. Therefore, it is important response (15), we evaluate the persis- Maxime Dougados, MD to assess the long-term outcomes of tence of low disease activity and remis- Please address correspondence to: treatment with biologic therapies, to sion over 7 years of treatment. For the Rene Westhovens, MD, PhD, ensure that they are safe, tolerable and first time, we also examine the propor- Department of Rheumatology, continue to offer clinical benefit. Low tion of patients in this trial showing sus- University Hospitals Leuven, disease activity and remission are now tained improvements (“normalisation”) Herestraat 49, more achievable goals in the treatment in physical function and quality of life 3000 Leuven, Belgium. of RA. Adapting treatment to target over time. E-mail: [email protected] these endpoints can result in significant Received on December 13, 2013; accepted benefits for patients, for example by re- Methods in revised form on March 12, 2014. ducing structural damage and promot- Study design and patients © Copyright CLINICAL AND ing normalisation of physical function The study design, conduct, and patient EXPERIMENTAL RHEUMATOLOGY 2014. (1-4). It is also important to ensure that population (ClinicalTrials.gov identi- patients adhere to therapy over time to fier NCT00162266) have been reported attain optimal treatment benefits. Re- previously (12, 14). All eligible patients tention rates achieved in clinical trials, entering the DB period were randomly especially in long-term extension (LTE) assigned (1:1:1) to receive a 30-minute studies, can provide an indication of IV infusion of abatacept (10 or 2 mg/ whether patients are likely to continue kg), or placebo, plus MTX, on Days 1, treatment. These data should also be 15, and 30, and every 4 weeks thereafter confirmed by real-world observations, (14). Patients completing the DB period such as registry data and daily practice were eligible to enter the open-label cohort follow-ups (5-8). LTE, during which they received fixed- Consistent safety and sustained efficacy dose IV abatacept (~10 mg/kg accord- of the selective co-stimulation modula- ing to weight range), plus MTX, every 4 tor, abatacept, which acts via the CD80/ weeks. All patients continued to receive CD86:CD28 co-stimulatory signal re- MTX during the LTE; adjustments quired for full T-cell activation (9), has in MTX and corticosteroid dose, ≤30 been demonstrated for up to 5 years in mg/week and 10 mg/day (prednisone patients with RA and an inadequate re- equivalent), respectively, were permit- sponse to methotrexate (MTX) (10-12). ted at the investigators’ discretion. Dur- In a Phase 2b trial, significantly more ing the LTE, patients were allowed any patients achieved an American College one of the following disease-modifying of Rheumatology (ACR) 20 response anti-rheumatic drugs (DMARDs) at the with intravenous (IV) abatacept (~10 investigators’ discretion: hydroxychlo- Conflict of interest: R. Westhovens has received speakers mg/kg) versus placebo at Month 6, and roquine, sulfasalazine, or leflunomide. bureau honoraria for Bristol-Myers Squibb. improvements in physical function and Patients treated for Mycobacterium tu- J.M. Kremer has received grant support, health-related quality of life (HRQoL) berculosis in the 3 years before study consultation, and speakers bureau were significantly greater with abata- initiation were excluded. honoraria from Bristol-Myers Squibb. cept compared with placebo at Month 6 P. Emery has received consulting fees (13). Clinical benefits observed during Safety assessments and speakers bureau honoraria from the 1-year double-blind (DB) period of Safety was evaluated monthly, on Bristol-Myers Squibb. A.S. Russell has received advisory board this trial (14) were sustained through 4 scheduled abatacept infusion days. and speakers bureau honoraria from years of open-label treatment, support- Assessments included all reported Bristol-Myers Squibb. ed by a retention rate of ~60% for pa- adverse events (AEs), serious AEs R. Alten has received research grants tients who entered the LTE (12). Here, (SAEs), discontinuations due to AEs, and honoraria from Bristol-Myers Squibb. we present the safety and efficacy of deaths, clinically significant changes E. Barré is an employee of Bristol-Myers IV abatacept plus MTX treatment over in vital signs, and physical examina- Squibb. 7 years from this Phase 2b trial in pa- tion and clinical laboratory test abnor- M. Dougados has received research grants and has participated at symposia tients with established RA and an inad- malities. All AEs were classified using and advisory boards organised by equate response to MTX, representing the Medical Dictionary for Regulatory Bristol-Myers Squibb, Pfizer, Abbott, UCB, the longest assessment of IV abatacept- Activities (MedDRA; version 11.1). Novartis, Sanofi-Aventis, and Lilly. treated patients with RA reported to Patients were monitored for acute in- 554 7-year abatacept plus methotrexate therapy / R. Westhovens et al. fusional reactions (reactions occurring derive Physical Component Summary that occurred ≤60 days after the last within 1 hour of infusion start). Auto- (PCS) and Mental Component Summa- infusion are included. Data are summa- immune events and acute-infusional ry (MCS) scores (20). Normalised PCS rised as frequencies and incidence rates AEs were prespecified based on a list or MCS scores were defined as scores (IRs), and are presented for the DB and of MedDRA-preferred terms. ≥50 (21). cumulative (DB plus LTE) periods. IRs The proportion of patients who were calculated as the number of pa- Efficacy assessments achieved multiple efficacy outcomes tients with the event of interest, divided Efficacy assessments were performed was also analysed, including patients by the total exposure during the speci- quarterly during the LTE. Treatment with both DAS28 (CRP)-defined re- fied treatment period, multiplied by 100 response was evaluated as the propor- mission and normalised mHAQ, and (events/100 patient-years of exposure). tions of patients experiencing a 20, 50, patients who were ACR50 responders A patient’s contribution to the exposure or 70% improvement in ACR criteria and achieved each of the following: in the IR of each AE ended at the time (ACR20, -50, or -70, respectively) (16). DAS28 (CRP) remission, and normal-