Orencia (abatacept) for Rheumatoid Arthritis Media backgrounder What is Orencia (abatacept)? Orencia (abatacept) is the first biologic agent to be available in both an intravenous (IV) and a self-injectable, subcutaneous (SC) formulation. 1 Abatacept, in either injectable formulation (intravenous or subcutaneous), is a treatment designed to reduce the signs and symptoms, reduce the progression of joint damage and improve physical function in adult RA patients. 1 In Europe, it is indicated for use in combination with methotrexate (MTX) to treat moderate to severe active rheumatoid arthritis in adults who have had an inadequate response to a disease-modifying antirheumatic drug (DMARD), including MTX or a tumour necrosis factor (TNF) antagonist (also known as an anti-tnf). 1 In addition, intravenous (IV) abatacept is approved for use in paediatric patients six years of age and older with polyarticular juvenile idiopathic arthritis (JIA) who have responded inadequately to other medicines including at least one tumour necrosis factor (TNF) antagonist. 1 How does abatacept work? Abatacept is a biologic Disease Modifying Anti-Rheumatic Drug (bdmard) (also known as a biologic). Synthetic (or conventional) DMARDs and biologic DMARDs are designed to reduce damage to joints in diseases such as RA by targeting molecules on the cells of the immune system, the joints, and fluids secreted from joints that cause inflammation. 2 Abatacept has a mechanism of action that targets the immune system early in the inflammation cascade, by selectively modulating T-cell activation. 1 It works by selectively modulating the second costimulatory signal, which is required for full activation of T-lymphocytes expressing CD28. 1 T-cells (or T lymphocytes) belong to a group of white blood cells, known as lymphocytes, which play an important role in the body s immune response. They are distinguished from other lymphocytes by the presence of T-cell receptors (TCR) on their surface. T- cells are thought to play a major role in the development of RA. 3 1
There are many types of biologics: those which inhibit a specific cytokine such as tumour necrosis factor, interleukin-1, interleukin-6 and those which target cell surface molecules on T or B lymphocytes. Fig 1. Adapted from Choy et al. 4 Abatacept works on the abnormal functioning of the immune system by targeting components of the inflammatory cascade How is abatacept administered? Abatacept is available in a subcutaneous (SC) and also an intravenous (IV) infusion formulation. Abatacept SC: o The subcutaneous formulation is a fixed 125 mg dose administered weekly through an injection under the skin following a single IV loading dose of approximately 10 mg/kg.1 Patients who are unable to receive an infusion may initiate weekly injections of subcutaneous abatacept without an intravenous loading dose. Patients transitioning from abatacept intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose. 1 Abatacept intravenous (IV) infusion: o The intravenous formulation is administered as a 30-minute intravenous infusion at a fixed dose based on weight range approximating 10mg/kg. Initially it is administered at day 0, then at two weeks, four weeks and then every four weeks thereafter. 1 2
Benefits of Abatacept In the AMPLE study i, subcutaneous abatacept showed, as compared to adalimumab: o a rapid onset of action and sustained response over 12 months 5 o effectively reduces radiographic progression of RA over 12 months 5 o effectively treats RA without compromising tolerability 5 Abatacept is an effective RA treatment with a favourable safety profile5,6 Abatacept is the only biologic therapy for RA approved for administration in both SC and IV form, offering physicians and their patients more choice. Clinical evidence for Abatacept The efficacy and safety profile of abatacept was studied through a rigorous clinical trial programme that has included more than 5,000 patients. o The clinical development programme for abatacept IV included six studies: Phase IIb trial which compared the safety and efficacy of abatacept 2mg/kg ii and 10mg/kg in combination with MTX to placebo in combination with MTX in RA patients with a previous inadequate response to MTX. 7 AIM (Abatacept in Inadequate responders to MTX), which compared the clinical efficacy and safety of abatacept (10mg/kg) in combination with MTX to MTX in combination with placebo, in patients who had a previous inadequate response to methotrexate. 8 ATTEST (AbaTacepT versus infliximab in MTX inadequate response population) which was a randomised double-blind study to assess the efficacy and safety of abatacept or infliximab versus placebo in patients who had an inadequate response to MTX. 9 ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders), which compared the efficacy and safety of abatacept in combination with nonbiologic DMARDs to non-biologic DMARDs alone in patients with an inadequate efficacy response to TNF antagonists. 10 AGREE (Abatacept study to Gauge Remission and joint damage progression in MTX naïve iii patients with Early Erosive RA) which assessed remission and joint damage progression in MTX naïve patients treated with abatacept plus MTX compared with MTX alone. 11 ASSURE (Abatacept Study of Safety in Use with other RA therapies), which studied the safety of abatacept compared to placebo when used in combination with a variety of biologic iv and non-biologic DMARDs. 12 i Please note that the AMPLE study was not part of the regulatory filing. No IV loading dose was used in AMPLE, which is different from the currently approved posology. AMPLE stands for Abatacept Versus Adalimumab Comparison in Biologic-Naïve rheumatoid arthritis (RA) Subjects With Background Methotrexate. ii Please note that the 2mg/kg dose is not an approved dose. iii Please note that abatacept is not approved in MTX-naïve patients. iv Please note that abatacept is not approved for use with other biologic DMARDs. 3
o The efficacy and safety profiles of abatacept SC were also investigated in a large development program consisting of six clinical trials that has included more than 2,500 patients. These included: A phase II dose-finding pharmacokinetics (PK) study which investigated a variety of dosing regimens for SC abatacept to assess the PK, safety and immunogenicity. 13 ACQUIRE, a large phase III trial, which demonstrated non-inferiority of abatacept SC when compared to abatacept IV with respect to ACR 20 responses following 6 months of treatment both in combination with MTX. 14 ATTUNE (Abatacept in subjects who switch from intravenous to subcutaneous therapy) investigated the safety, tolerability and efficacy of patients who switched from long-term IV abatacept to subcutaneous abatacept. 15 ALLOW (Evaluation of Abatacept Administered SubcutaneousLy in AduLts With Active RheumatOid Arthritis: Impact of Withdrawal and Reintroduction on Immunogenicity, Efficacy and Safety) assessed the effect of temporary withdrawal and re-introduction of SC abatacept on immunogenicity, safety and efficacy in patients with RA responding to treatment. 16 ACCOMPANY (AbataCept in SubjeCts with RheumatOid Arthritis AdMinistered Plus or Minus Background MTX SubcutANeouslY) assessed the immunogenicity, steady state trough level and safety of subcutaneous abatacept, administered with or without background MTX in patients with rheumatoid arthritis. 17 These results formed the basis of the regulatory submission to the EMA for abatacept s use in a SC formulation. It is the first biologic agent available in both an IV and a SC formulation, offering an alternative mode of action (MOA) to anti-tnf agents for patients who have had an inadequate response to MTX or to an anti-tnf. References: 1 Orencia SMPC. Available at: http://www.medicines.org.uk/emc/medicine/19714/spc/orencia+250+mg+powder+for+concentrate+for+solution+f or+infusion/ Last accessed: 26 September 2012 2 Arthritis Research UK, What is arthritis? Available at: http://www.arthritisresearchuk.org/~/media/files/arthritisinformation/conditions/2020-what-is-arthritis.ashx Accessed 17 July 2012 3 Gutcher I, et al. J Clin Invest. 2007;117(5):1119 1127 4 Choy E and Panatyi G. N. Engl. M Med. 2001;344: 907-916 5 Schiff M, Fleischmann R, Weinblatt M, et al. EULAR; 6-9 June 2012; Berlin, Germany. Abstract 3409 6 Moore LA, Kaufman MD, Algozzine R, et al. Rehabil Nurs 2007;32(6):227 232 7 Kremer J, et al. Arthritis Rheum. 2005 Aug;52(8):2263-71 8 Kremer J, et al. Ann Intern Med. 2006 Jun 20;144(12):865-76 9 Schiff M, et al. Ann Rheum Dis. 2008;67:1096 103 10 Genovese MC, et al. Ann Rheum Dis. 2008 Apr;67(4):547-54 11 Bathon J, et al. Ann Rheum Dis. 2011 Nov;70(11):1949-56 12 Weinblatt M, et al. Arth & Rheum 2006;54(9): 2807-16 13 Corbo M, et al. Ann Rheum Dis 2009;68(Suppl3):574.Abstract SAT0101 14 Genovese M, et al. Arthritis & Rheumatism, 2011;63(10): 2854-64 15 Keystone E, et al. Ann Rheum Dis, 2012;71: 857-861 16 Kaine J, et al. Ann Rheum Dis, 2012;71: 38-44 4
17 Nash P, et al. Arthritis & Rheumatism, 2009;60(Suppl 10). Abstract 1692 5