Orencia (abatacept) is a soluble fusion protein, which links the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). It is produced through recombinant DNA technology in mammalian cells. The drug has activity as a selective costimulation modulator with inhibitory activity on T lymphocytes.

Orencia is specifically indicated for the second line reduction of the signs and symptoms of moderate-to-severe active rheumatoid arthritis, inducing inducing major clinical response, slowing the progression of structural damage, and improving physical function in adult patients who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate or TNF antagonists. It is indicated both as a monotherapy and for use in combination with a continued regimen of DMARDs (not including TNF antagonists).

Orencia is supplied as a lyophilized powder for intravenous infusion in an individually packaged, single-use vial with a silicone-free disposable syringe. Recommended dosage is depended on body weight:

• Less than 132.3 lbs (60 kg): 500 mg
• 132.3 lbs to 220.5 lbs (60 kg to 100 kg): 750 mg
• More than 220.5 lbs (100 kg): 1 g

Treatment was to be administered via 30-minute infusion. The second dose should be administered 2 to 4 weeks after the first, then every 4 weeks thereafter.

FDA Approval
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

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)
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• 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).

Ongoing Study Commitments

• Your deferred pediatric study required under section 2 of the Pediatric Research Equity Act (PREA) is considered a required postmarketing study commitment. The status of this postmarketing study shall be reported annually according to 21 CFR 601.70. This commitment is the deferred pediatric study under PREA for the treatment of polyarticular course juvenile rheumatoid arthritis in pediatric patients ages 2 to 16. We note that a study responsive to this commitment is underway.
  Final report submission date: November 30, 2006
• Protocol IM101045A, a pharmacoepidemiology study to assess the short term (2 years) and potential long-term (4 years) risk of hospitalization due to infection (all hospitalized infections, hospitalized pneumonia, and all opportunistic infections) among patients with RA treated with abatacept in comparison to other DMARDs within a large cohort of individuals with commercial health insurance. This study will also characterize patients receiving abatacept and monitor any off-label use. The study will be completed per the following timetable:
  Protocol submission date: January 31, 2006
  Enrollment completion date: December 31, 2011
  Observation period completion date: December 31, 2015
  Final report submission date: December 31, 2016
• Protocol IM101045B, proposed as an observational prospective pharmacoepidemiology cohort study to assess the short and long-term risk of malignancies and infection in patients with RA treated with abatacept in comparison to other DMARDs within an existing registry containing patients with rheumatoid arthritis. Follow-up will be for at least 5 years after the last patient is enrolled. The study will be completed per the following timetable:
  Protocol submission date: January, 31 2006
  Enrollment completion date: June 1, 2009
  Observation period completion date: June 31, 2014
  Final report submission date: December 31, 2016
• To continue the open label extensions of 5 studies (IM101-100, IM101-101, IM101-102, IM101-029, IM101-031) to obtain data and perform appropriate safety analyses for 5 years’ exposure to abatacept for 1000-1500 patients according to the following timetable:
  Open label extension completion date: September 30, 2009
  Integrated Safety Analysis submission date: June 30, 2010

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

• Headache
• Nasopharyngitis
• Dizziness
• Cough
• Back Pain
• Hypertension
• Dyspepsia
• Urinary tract infection

Administration of Orencia in patients with chronic obstructive pulmonary disorder (COPD) has associated with exacerbation and increased incidence of COPD symptoms. Patients suffering from both rheumatoid arthritis and COPD who elect to pursue Orencia therapy should monitor symptoms carefully, and in collaboration with their physicians.

In addition, Orencia has demonstrated or is predicted to demonstrate negative interactions with other classes of drugs. First, clinical data indicate that concomitant use of TNF antagonists does yield a significant enhancement of efficacy compared to either drug alone, and is associated with increased rates of infection (68%) and serious infection (4.4%), compared to TNF antagonists alone (43% and 0.8%, respectively). As such, concomitant use of Orencia and TNF antagonists is not recommended, and patients should be monitored for signs of infection when transitioning from one drug to the other. Further, based on Orencia's mechanism of action, it is predicted that the efficacy of vaccinations may be reduced while receiving the drug. Data are not available reagarding secondary transmission of infection in patients receiving live vaccines while on Orencia therapy. It is recommended that patients not receive live vaccines while on Orencia therapy or within 3 months of its discontinuation.

Orencia is a selective costimulation modulator, shown to inhibit Tcell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis.

Emery P. Abatacept has beneficial effects in rheumatoid arthritis patients with an inadequate response to anti-TNFalpha therapy Clinical and Experimental Rheumatology 2005 Nov-Dec;23(6):767-768

Kremer JM. Selective costimulation modulators: a novel approach for the treatment of rheumatoid arthritis Journal of Clinical Rheumatology 2005 Jun;11(3 Suppl):S55-62

Kliwinski C, Kukral D, Postelnek J, Krishnan B, Killar L, Lewin A, Nadler S, Townsend R. Prophylactic administration of abatacept prevents disease and bone destruction in a rat model of collagen-induced arthritis Journal of Autoimmunology 2005 Nov;25(3):165-71. Epub 2005 Oct 25

Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, Birbara C, Box J, Natarajan K, Nuamah I, Li T, Aranda R, Hagerty DT, Dougados M. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition New England Journal of Medicine 2005 Sep 15;353(11):1114-23. Erratum in: New England Journal of Medicine 2005 Nov 24;353(21):2311

For additional information regarding Orencia or rheumatoid arthritis, please visit the Orencia web page.