Orencia (abatacept) - 4 indications

Scroll down for information on each indication:

• for the treatment of rheumatoid arthritis; approved December 2005
• for the treatment of moderately to severely active polyarticular juvenile idiopathic arthritis; approved April 2008
• for the treatment of adults with active psoriatic arthritis; approved July of 2017
• for the prevention of acute graft versus host disease; approved December of 2021

General Information

Orencia (abatacept) is a selective T cell co-stimulation modulator.

Orencia is specifically indicated for the following:

• for the treatment of adult patients with moderately to severely active rheumatoid arthritis
• for the treatment of patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis
• for the treatment of adult patients with active psoriatic arthritis
• for the prevention of acute graft versus host disease

Orencia is supplied as a lyophilized powder for intravenous or subcutaneous administration. Scroll down for specific dosing/administration for each indication.

Mechanism of Action

Orencia (abatacept), a selective co-stimulation modulator, inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T lymphocytes are implicated in the pathogenesis of RA, pJIA and PsA and are found in the synovium of patients with RA, pJIA and PsA.

Side Effects

Adverse effects associated with the use of Orencia may include, but are not limited to, the following:

• headache
• upper respiratory tract infection
• nasopharyngitis
• nausea

Indication 1 - rheumatoid arthritis

approved December 2005

Dosing/Administration

For adult patients with RA, administer as an intravenous infusion or as a subcutaneous injection. Orencia may be used as monotherapy or concomitantly with disease modifying antirheumatic drugs (DMARDs) other than JAK inhibitors or bDMARDs. 

Intravenous Dosing Regimen

Reconstitute Orencia lyophilized powder and administer after dilution as a 30-minute intravenous infusion utilizing the weight range-based dosing specified below. Following the initial intravenous infusion, administer as an intravenous infusion at 2 and 4 weeks and every 4 weeks thereafter. Each vial contains 250 mg of abatacept.

Body Weight	Dose	Number of Vials
Less than 60 kg	500 mg	2
60 to 100 kg	750 mg	3
More than 100 kg	1000 mg	4

 

Subcutaneous Dosing Regimen

Prior to the first subcutaneous dose, may administer an optional loading dose as a single intravenous infusion (as per body weight categories in Table above). If an intravenous loading dose is used, administer the first subcutaneous injection within one day of the infusion. Administer Orencia 125 mg in prefilled syringes or in Orencia ClickJect autoinjector by subcutaneous injection once weekly. For patients switching from Orencia intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Clinical Trial Results

Approval of Orencia was supported by five randomized, double-blind, placebo-controlled clinical trials. In all five studies, subjects received treatments with Orencia or placebo at weeks 0, 2, and 4, then every 4 weeks thereafter.

Study I

The first trial enrolled 122 patients with active rheumatoid arthritis who had failed at least one regimen of etanercept or a non-biologic DMARD. Subjects received one of three doses of Orencia monotherapy (0.5 mg/kg, 2 mg/kg, or 10 mg/kg) or placebo for 8 weeks. Trial data increased the portion of subjects achieving 20%, 50% and 70% reductions in American College of Rheumatology (ACR) symptom severity scores in the 10 mg/kg dosing group (n=32 subjects) at 3 months, compared to the placebo group (n=32 subjects):

• ACR 20 = 53% for 10 mg/kg Orencia vs. 31% for placebo
• ACR 50 = 16% for 10 mg/kg Orencia vs. 6% for placebo
• ACR 70 = 6% for 10 mg/kg Orencia vs. 0% for placebo

Study II

This trial enrolled patients who had demonstrated an inadequate response to methotrexate monotherapy (MTX). Subjects received one of two doses of Orencia (2 mg/kg or 10 mg/kg) or placebo in additioned to maintained treatment with MTX for 12 months. Results indicated that the addition of Orencia to MTX produced a significant improvement from baseline on the Health Assessment Questionaire Disability Index (HAQ-DI) at 1 year, compared to MTX plus placebo (plus 0.40 points for Orencia, vs. 0.15 points for placebo; p<0.001). Further, Orencia improved quality of life scores on the Physical Component Summary (PCS) diagnostic scale, Mental Compnent Summary (MCS) diagnostic scale, and all 8 domains of the SF-36 diagnostic questionnaire at 6 and 12 months.

Study III

This trial, like Study II, enrolled patients who had failed MTX therapy. 638 patients received Orencia or placebo (dose based on body weight; see General Information, above) for 12 months, in additioned to maintained treatment with MTX. Trial data yielded significant improvements (p<0.001 for all values) in ACR 20, ACR 50, and ACR 70 rates at 3, 6 and 12 months, and in rates of Major Clinical Response (ACR 70 maintained continuously for 6 months):

• 3-month ACR 20 = 62% for Orencia vs. 37% for placebo
• 3-month ACR 50 = 32% for Orencia vs. 8% for placebo
• 3-month ACR 70 = 13% for Orencia vs. 3% for placebo
• 6-month ACR 20 = 68% for Orencia vs. 40% for placebo
• 6-month ACR 50 = 40% for Orencia vs. 17% for placebo
• 6-month ACR 70 = 20% for Orencia vs. 7% for placebo
• 12-month ACR 20 = 73% for Orencia vs. 40% for placebo
• 12-month ACR 50 = 48% for Orencia vs. 18% for placebo
• 12-month ACR 70 = 29% for Orencia vs. 6% for placebo
• Major Clinical Response: 14% for Orencia vs. 2% for placebo

Orencia also significantly improved a number of secondary measures at 6 months, including number of tender joints, number of swollen joints, pain, HAQ-DI, patient global assessment, physician global assessment, C-reactive protein levels (p<0.001 for all endpoints) and radiographic structural joint health scores (p<0.03 for three radiographic endpoints).

Study IV

This trial enrolled patients who had failed to respond well on a treatment regimen with a TNF antagonist. 489 patients received Orencia or placebo (dose based on body weight; see General Information, above) for 6 months; TNF-antagonist treatment was discontinued prior to treatment with Orencia, but continued treatment with other DMARDs was allowed to continue. Trial data yielded significant improvements in ACR 20, ACR 50, and ACR 70 rates at 3 and 6 months:

• 3-month ACR 20 = 46% for Orencia vs. 18% for placebo (p<0.001)
• 3-month ACR 50 = 18% for Orencia vs. 6% for placebo (p<0.01)
• 3-month ACR 70 = 6% for Orencia vs. 1% for placebo (p<0.05)
•  
• 6-month ACR 20 = 50% for Orencia vs. 20% for placebo (p<0.001)
• 6-month ACR 50 = 20% for Orencia vs. 4% for placebo (p<0.001)
• 6-month ACR 70 = 10% for Orencia vs. 2% for placebo (p<0.01)

Orencia also significantly improved a number of secondary measures at 6 months, including number of tender joints, number of swollen joints, HAQ-DI, patient global assessment, physician global assessment, C-reactive protein levels (p<0.001 for all endpoints) and pain (p<0.01).

Study V

Study V was designed to investigate the safety of Orencia therapy in a number of clinically relevant circumstances, including treatment in combination with other approved DMARDs and in patients with comorbid contditions. Patients received Orencia or placebo (dose based on body weight; see General Information, above) for 12 months, in addition to maintained therapy. The drug produced HAQ-DI response similar to that observed in Studies II and III. Exacerbations of respiratory symptoms was noted in patients with comorbid COPD (see Side Effects section below).

Indication 2 -  moderately to severely active polyarticular juvenile idiopathic arthritis

approved April 2008

Dosing/Administration

Orencia can be administered as an intravenous infusion (only patients 6 years of age and older) or a subcutaneous injection (only patients 2 years of age and older). Orencia may be used as monotherapy or concomitantly with methotrexate.

Intravenous Dosing Regimen

Administer Orencia as a 30-minute intravenous infusion based on body weight:

• If less than 75 kg, administer a dose of 10 mg/kg
• If 75 kg or greater, administer as per the recommendations in the table above for adults with RA (follow the adult intravenous dosing regimen), not to exceed a maximum dose of 1000 mg. Following the initial intravenous infusion, administer infusions at 2 and 4 weeks and every 4 weeks thereafter. Immediately discard any unused portion in the vials.

Subcutaneous Dosing Regimen

Administer Orencia for subcutaneous injection, without an intravenous loading dose, utilizing the weight range-based dosing as specified in the table below. Subsequently administer once weekly.

Body Weight of Pediatric Patient (2 yrs of age and over)	Dose (once weekly)
10 to less than 25 kg	50 mg
25 to less than 50 kg	87.5 mg
50 kg or more	125 mg

Clinical Trial Results

The FDA approval of Orencia for this indication was based on the results of a three-part study including an open-label extension. The study enrolled 190 pediatrics with moderately to severely active polyarticular JIA who had an inadequate response to one or more DMARDs, such as MTX or TNF antagonists.

In Period A, an open-label, lead-in phase, patients received 10 mg/kg (maximum 1000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed utilizing the ACR Pediatric 30 definition of improvement,6 defined as =30% improvement in at least 3 of the 6 JIA core set variables and =30% worsening in not more than 1 of the 6 JIA core set variables. Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase, Period B, and received either Orencia or placebo for 6 months or until disease flare.

Period A
At the conclusion of Period A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively. Pediatric ACR 30 responses were similar in all subtypes of JIA studied.

Period B
During this double-blind randomized withdrawal phase, Orencia-treated patients experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among patients continuing on Orencia was less than one third than that for patients withdrawn from Orencia treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]).

Among patients who received Orencia throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR 30/50/70 responders remained consistent for 1 year.

Indication 3 - adults with active psoriatic arthritis

approved July of 2017

Dosing/Administration

For adult patients with psoriatic arthritis, administer as an intravenous infusion or a subcutaneous injection. Orencia may be used with or without non-biologic DMARDs.

Intravenous Dosing Regimen

Administer Orencia as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in the table above for adults with rheumatoid arthritis. Following the initial intravenous administration, administer an intravenous infusion at 2 and 4 weeks and every 4 weeks thereafter.

Subcutaneous Dosing Regimen

Administer 125 mg of Orencia subcutaneously once weekly (no intravenous loading dose is needed). For patients switching from Orencia intravenous infusions to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Clinical Trial Results

FDA approval was based on two randomized, double-blind, placebo-controlled studies (Studies PsA-I and PsA-II) in 594 adult patients with disease duration more than seven years. Patients had active Psoriatic Arthritis (≥ 3 swollen joints and ≥ 3 tender joints) despite prior treatment with DMARD therapy and had one qualifying psoriatic skin lesion of at least 2 cm in diameter. In PsA-I and PsA-II, 37% and 61% of patients, respectively, were treated with TNF inhibitors (TNFi) previously.1 The primary endpoint for both PsA-I and PsA-II was the proportion of patients achieving ACR 20 response at Week 24 (Day 169).1

In PsA-I, a dose-ranging study, 170 patients received study drug IV at Days 1, 15, 29, and then every 28 days thereafter in a double-blind manner for 24 weeks, followed by open-label Orencia every 28 days. Patients were randomized to receive placebo or Orencia 3 mg/kg, 10 mg/kg (weight range-based dosing: 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg), or two doses of 30 mg/kg followed by weight range-based dosing of 10 mg/kg without escape for 24 weeks. Patients were allowed to receive stable doses of concomitant methotrexate, low dose corticosteroids (equivalent to ≤ 10 mg of prednisone) and/or NSAIDs during the trial. At enrollment, approximately 60% of patients were receiving methotrexate.

In PsA-II, 424 patients were randomized 1:1 to receive weekly doses of SC placebo or Orencia 125 mg SC without a loading dose for 24 weeks, followed by open-label Orencia 125 mg SC weekly. Patients were allowed to receive stable doses of concomitant methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, low dose corticosteroids (equivalent to ≤ 10 mg of prednisone) and/or NSAIDs during the trial. At randomization, 60.4% of patients were receiving methotrexate.

A higher proportion of patients treated with Orencia 10 mg/kg IV or 125 mg SC achieved an ACR20 response at Week 24 compared to placebo, 47.5% versus 19.0% and 39.4% versus 22.3%, respectively. Responses were seen regardless of prior anti-TNFi treatment and regardless of concomitant non-biologic DMARD treatment. Improvements in enthesitis and dactylitis were seen with Orencia treatment at Week 24 in both IV and SC.

Indication 4 - for the prevention of acute graft versus host disease

Approved December of 2021

Dosing/Administration

Before administering Orencia, administer recommended antiviral prophylactic treatment for Epstein-Barr Virus (EBV) reactivation, and continue for six months following HSCT. In addition, consider prophylactic antivirals for Cytomegalovirus (CMV) infection/reactivation during treatment and for six months following HSCT.

Intravenous Dosing Regimen For patients 6 years and older, administer Orencia 10 mg/kg (maximum dose of 1,000 mg) as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation. For patients 2 to less than 6 years old, administer Orencia 15 mg/kg as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by 12 mg/kg as an intravenous infusion over 60 minutes on Days 5, 14, and 28 after transplantation.

Clinical Trial Results

FDA approval for Orencia in this indication was based on two different studies, the phase 2 GVHD-1 trial (also known as ABA2) and GVHD-2.

GVHD-1 was a multicenter, two cohort trial (a double-blind, placebo-controlled cohort and open-label, single-arm cohort) of patients ages 6 years and older who underwent HSCT from a matched (n=142) or 1 allele-mismatched (n=43) URD. Orencia was added to a standard GvHD prophylactic regimen (CNI and MTX). Results showed that when Orencia was added, there was a significant reduction in severe aGvHD and associated morbidity without an increase in disease relapse. Patients who received Orencia saw a 98% overall survival rate compared to 75% for patients who received standard immunosuppression alone. Patients with severe disease who received Orencia saw a 97% overall survival rate compared to 84% for placebo. For moderate-severe aGVHD-free survival, patients who received Orencia saw a 50% rate compared to 32% for patients who received a placebo.

GVHD-2 – a second clinical study using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) – was also conducted to analyze outcomes of Orencia in combination with CNI and MTX (n=54) for aGvHD prophylaxis in comparison to that of recipients who received only CNI and MTX (n=162), in patients 6 years of age or older undergoing HSCT from a 1 allele-mismatched URD between 2011 and 2018. The Orencia-treated group (n=54) included 42 patients from GVHD-1, in addition to 12 patients treated with Orencia outside of GVHD-1. The comparator group (n=162) was randomly selected in a 3:1 ratio to the Orencia-treated group from the CIBMTR registry from patients who had not received Orencia during the study period. Efficacy was based on OS at Day 180 post-HSCT. The OS rate at Day 180 in the Orencia in combination with CNI and MTX group was 98% and the OS rate at Day 180 in the CNI and MTX group was 75%.