Pharmacology Update

Abatacept Infusion (Orencia®)

By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationships to this field of study.

A novel T-cell inhibitor has been approved for the treatment of rheumatoid arthritis. Abatacept is the first selective modulator of a costimulatory signal involved in T-cell activation (costimulatory blocker). The drug is a soluble fusion protein of cytotoxic T-lymphocyte-associated antigen 4 linked to immunoglobulin G1. It is marketed by Bristol-Myers Squibb as Orencia®.

Indications

Abatacept is indicated for reducing signs and symptoms, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs) (eg, methotrexate, or tissue necrosis factor [TNF] antagonists). It may be used as monotherapy or with DMARDs but not TNF antagonists or anakinra.1

Dosage

Abatacept is given as a 30-minute intravenous infusion. The dose is based on the body weight of the patient, 500 mg for those < 60 kg, 750 mg (60-100 kg) and 1 gm for those > 100 kg. After the initial dose, a dose should be given at 2 and 4 weeks and every 4 weeks thereafter. Patients should be skin tested for tuberculosis and should not receive any live vaccines while on treatment and for 3 months after discontinuation.1

Potential Advantages

Abatacept offers a new agent with a different mechanism of action and has shown clinical and functional benefit in patients with rheumatoid arthritis who have not responded to DMARDs or (TNF) inhibitors.1-3 Improvements in signs and symptoms, physical function, and quality of life were reported.

Potential Disadvantages

As with other biological immunomodulators, abatacept may increase the risk of infections and malignancies. Serious infections were more frequent with abatacept than placebo (3% vs 1.9%) as well as lung cancer (0.21 cases per 100 patient-years) and lymphoma (0.10 per 100 patient-years), approximately 3.5 times higher than expected in an age gender-matched population).1 Infusion related adverse events include dizziness, headache, and hypertension. Two cases (out of 2688 treated patients) of anaphylaxis or anaphylactoid reactions were reported. Abatacept requires 30-minute intravenous infusions. Patients with COPD appeared more likely to experience severe adverse events with abatacept compared to placebo (27% vs 6%) including COPD exacerbation and pneumonia.1

Comments

Abatacept is a selective costimulator modulator that inhibits T cell activation by binding to CD80 and CD86 on the surface of antigen presenting cells. The binding of these ligands to CD28 of T-cells is required for full T cell activation.4 This inhibition results in decreased T cell proliferation and inhibition of the production of tissue necrosis factor (TNF), interferon, and interleukine-2.1 Efficacy and safety of abatacept were established in 5 randomized, 4-to-12 month, placebo-controlled trials. Trial participants were rheumatoid arthritis patients who had not responded to a DMARD, methotrexate, or a TNF inhibitor. Abatacept was added to methotrexate or replaced the DMARD or TNF inhibitor. Outcomes were assessed by 20%, 50%, and 70% improvement based on American College of Rheumatology (ACR) criteria and Health Assessment Questionnaire disability index. Abatacept generally showed significantly higher rates of response and improvement in physical function compared to placebo. In a large (n = 638) 12-month study in patients who had inadequate response to methotrexate, ACR 20, 50, and 70 at 12 months were 73%, 48%, and 29% for abatacept (weight-based dosing) plus methotrexate and 40%, 18%, and 6% respectively for placebo plus methotrexate.1 The combination also showed radiographic evidence of slowing of progression of structural damage and improvement in physical function. In a 6-month study (n = 389) in patients who had inadequate response to an anti-TNF drug, ACR 20, 50, 70 were 50%, 20%, and 10% for abatacept (weight-based dosing) plus DMARDs vs. 20%, 4%, and 2% for placebo plus DMARDs.1,2 Abatacept is generally well tolerated with a higher incidence of infusion-related adverse events and serious infections. The potential increased risk of malignancies is not clear. Patients with COPD appeared to be more susceptible to adverse events. The supply of abatacept is limited and is distributed by designated specialty pharmacies. The cost of abatacept is similar to that of anti-TNF drugs and anakinra.5

Clinical Implications

Abatacept offers a drug with a different mechanism of action for patients who have not responded adequately to existing therapy. It can be used as monotherapy or in combination with other DMARDs but not with an anti-TNF drug or anakinra.

References

1. Orencia Product Information. Bristol-Myers Squibb Company. December 2005.

2. Genovese MC, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353:1114-1123; Erratum in: N Engl J Med. 2005;353:2311.

3. Kremer JM, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52:2263-2271; Erratum in: Arthritis Rheum. 2005;52:3321.

4. Emery P. The therapeutic potential of costimulatory blockade with CTLA4Ig in rheumatoid arthritis. Expert Opin Investig Drugs. 2003;12:673-681.

5. The Medical Letter. Abatacept (Orencia) for rheumatoid arthritis. 2006;48:17-18.