Abatacept (Orencia) injection for intravenous use is a soluble fusion protein that is produced by recombinant deoxyribonucleic acid (DNA) technology. It is a selective co-stimulation modulator that consists of human cytotoxic T-lymphocyte-associated antigen-4 linked to a modified portion of human immunoglobulin G1 (IgG1).
The activation of T lymphocytes has been implicated in the pathogenesis of rheumatoid arthritis (RA), polyarticular juvenile idiopathic arthritis (pJIA), and psoriatic arthritis (PsA). Because abatacept (Orencia) injection for intravenous use interrupts T-lymphocyte activation, it has been studied to be effective for the treatment of RA and PsA, and is frequently used in the management of adults and children with pJIA.
The American College of Rheumatology (ACR) guidelines for the treatment of RA recommend that newly diagnosed individuals with RA begin treatment with disease-modifying antirheumatic drugs (DMARDs). DMARDs act to slow down disease progression, and some act with mild chemotherapeutic action, causing immunosuppression. The ACR Guidelines for the treatment of pJIA recommend nonsteroidal anti-inflammatory drugs (NSAIDs) or DMARDs as initial therapy. The ACR Guidelines for PsA initial treatment recommend methotrexate (MTX) in individuals with less active disease and biologic TNFi with severe disease.
DMARDs can be subdivided into the traditional small-molecular-mass, chemically synthesized non-biologic DMARDs (such as, but not limited to, methotrexate, sulfasalazine, azathioprine, leflunomide, hydroxychloroquine sulfate, and cyclosporine) and biologic DMARDs. Examples of biologic DMARDs include, but are not limited to, infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), anakinra (Kineret), golimumab (Simponi, Simponi Aria), tocilizumab (Actemra), and rituximab (Rituxan).
Abatacept (Orencia) is available in two forms: injection for intravenous use and injection for subcutaneous use.
Acute Graft versus Host Disease (aGVHD), Prophylaxis
The safety and efficacy of abatacept (Orencia) injection for intravenous use, in combination with a calcineurin inhibitor (CNI) (e.g., cyclosporine, tacrolimus) and MTX for the prophylaxis of aGVHD was accessed in two clinical studies.
The first was a Phase 2, double-blind, multicenter, two-cohort clinical study (GVHD-1) in individuals 6 years of age and older who underwent hematopoietic stem cell transplantation (HSCT) from a matched or one-allele-mismatched unrelated donor. The two cohorts in GVHD-1 included:
- An open-label, single-arm study of 43 individuals who underwent a 7 of 8 human leukocyte antigen (HLA)-matched HSCT (7 of 8 cohort)
- A randomized (1:1), double-blind, placebo-controlled study of 142 individuals who underwent an 8 of 8 HLA-matched HSCT who received abatacept (Orencia) or placebo in combination with a CNI and MTX (8 of 8 cohort).
In both cohorts, individuals in the abatacept (Orencia) group received 10 mg/kg (1000 mg maximum dose) IV over 60 minutes on the day before transplantation (Day −1), followed by administration on Days 5, 14, and 28 after transplantation. In cohort 1, an exploratory analysis revealed the following rates of grade III to IV GFS (95%), grade II to IV GFS (53%), and overall survival (98%) at day 180 posttransplantation. In cohort 2, at Day 180 posttransplantation, there was significantly improved overall survival (OS) rate in the abatacept (Orencia) + CNI + MTX group of 97% compared to 84% for the placebo group. There was also a significantly improved rate of aGVHD-free survival (GFS) for moderate-to-severe (grade II-IV) aGVHD in the abatacept (Orencia) + CNI + MTX group (50%), compared to the placebo group (32%). However, severe (grade III-IV) aGVHD-free survival (GFS) was not significantly improved in the abatacept (Orencia) group (87%) compared to those who received a placebo (75%).
The second clinical study, GVHD-2, used real-world data from the Center for International Blood and Marrow Transplant Research (CIBMTR). The study analyzed the outcomes of individuals 6 years of age or older who underwent HSCT from a one-allele-mismatched unrelated donors between 2011 and 2018 and received abatacept (Orencia) in combination with a CNI and MTX, versus a CNI + MTX alone, for the prophylaxis of aGVHD. The abatacept (Orencia) + CNI + MTX group (n=54) included 42 individuals from the GVHD-1 study, in addition to 12 individuals treated with abatacept (Orencia) outside of GVHD-1. The comparator group (n=162) received CNI + MTX alone, and were randomly selected in a 3:1 ratio to the abatacept (Orencia) + CNI + MTX group from the CIBMTR registry from individuals. The study measured overall survival (OS) 6 months after transplantation. Those in the abatacept (Orencia) + CNI + MTX group saw a 98% overall survival rate compared to 75% for those who received CNI + MTX alone.
The most common side effects of abatacept (Orencia) for prevention of aGVHD included anemia, hypertension, cytomegalovirus (CMV) reactivation/CMV infection, fever, pneumonia, nosebleed, decreased levels of specific white blood cells called CD4 lymphocytes, increased levels of magnesium in the blood, and acute kidney injury.
Polyarticular Juvenile Idiopathic Arthritis
The safety and efficacy of abatacept (Orencia) injection for intravenous use in the treatment of juvenile idiopathic arthritis (JIA) was assessed in a three-part study with individuals ages 6 years to 17 years with moderate to severely active pJIA with inadequate response to one or more DMARDs. The principal measure of clinical response in part A of this study was the ACR pediatric 30 definition of improvement (i.e., 30% or greater improvement in at least 3 of 6 and 30% or greater deterioration in no more than 1 of 6 core set criteria that include physician and child/parent global assessments, active joint count, limitation of motion, functional assessment, and erythrocyte sedimentation rate). Individuals with an "ACR pediatric 30" response at the end of part A were randomly assigned into part B, the double-blind phase. In part B, the primary endpoint was time to disease flare (defined as a 30% or greater deterioration in 3 of 6 and a 30% or greater improvement in no more than 1 of 6 core set criteria). At the end of part B, study participants treated with abatacept (Orencia) injection for intravenous use reported significantly fewer disease flares as compared to individuals treated with placebo. (Part C of the study was an open-label extension.)
At the conclusion of part A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively. During part B, study participants reported significantly fewer disease flares compared to placebo-treated study participants. Among study participants who received abatacept (Orencia) injection for intravenous use throughout the study period (part A, B and C), the proportion of pediatric ACR 30/50/70 responders remained consistent for 1 year.
The safety and efficacy of abatacept (Orencia) injection for intravenous use was assessed in a Phase 2, randomized, double-blind, multicenter, dose-ranging study of 170 adults with active arthritis (defined as the presence of three or more swollen joints and three or more tender joints), and active plaque psoriasis (with at least one qualifying target lesion of 2 cm or more in diameter). Participants had an inadequate response to DMARDs, including, but not limited to, MTX or anti-TNF agents. Participants were randomly assigned (1:1:1:1) to receive placebo or abatacept (Orencia) IV infusions at doses of 3 mg/kg, 10 mg/kg, or 30/10 mg/kg (two initial doses of 30 mg/kg, followed by 10 mg/kg) on days 1, 15, and 29 and then once every 28 days thereafter for 6 months. The primary endpoint of this study was ACR 20 response on day 169, resulting in 42% in those who received 30/10 mg/kg of abatacept (Orencia), 48% who received 10 mg/kg, 33% who received 3 mg/kg, and 19% who received placebo. Compared to placebo, the ACR20 responses were statistically significant for the 30/10 mg/kg (P = 0.022) and the 10 mg/kg (P= 0.006), but not the 3 mg/kg (P= 0.121) doses of abatacept (Orencia).
Genovese et al. (2011) performed a noninferiority study in the treatment of RA showing the therapeutic equivalence of abatacept (Orencia) dosing at 10 mg/kg IV every 4 weeks and 125 mg subcutaneously (SC) weekly. Further, the safety and efficacy of abatacept (Orencia), 125 mg weekly SC injection, was performed in a randomized, double-blind, Phase 3 study in the treatment of 424 adults with active PsA (as defined in previous study). Participants had an inadequate response or intolerance to one or more DMARDs, including, but not limited to, MTX or anti-TNF agents. Participants were randomly assigned (1:1) to receive placebo or abatacept (Orencia) subcutaneous 125 mg weekly for 24 weeks followed by open-label subcutaneous abatacept. As the primary endpoint, abatacept (Orencia) significantly increased ACR20 response versus placebo at week 24 (39.4% vs 22.3%; P<0.001).
Evidence of clinical benefit and safety of abatacept (Orencia) injection for intravenous use in the management of RA is based principally on the results of six randomized, double-blind, placebo-controlled clinical trials in adults (18 years of age or older) with the disease. Improvement in the signs and symptoms of RA after treatment with abatacept (Orencia) injection for intravenous use was consistently reported by the participants of the studies, according to the response rate measured by the ACR scores.
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.