Bristol-Myers Squibb's Orencia (abatacept)

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation of the joints. It affects approximately 2.1 million Americans, of whom 70% are women.¹ Onset usually is between 30 and 50 years of age, but the disorder can occur in children. Symptoms, developing over weeks to months, consist of fatigue, weakness, pain, stiffness, and swelling of the joints.¹

Traditional treatments include nonsteroidal anti-inflammatory drugs, corticosteroids, disease-modifying antirheumatic drugs (DMARDs; such as methotrexate [MTX]), and biological response modifiers (such as anti-tumor necrosis factor [TNF] therapy). The goals of current therapy include pain relief, preventing further loss of joint tissue, and improvement of patients' daily functioning.

In December 2005, Bristol-Myers Squibb received FDA approval for Orencia for the treatment of moderateto- severe RA. It is the first selective modulator of a costimulatory signal required for full T-cell activation.

Pharmacology

Activated T-cells are found in the synovial fluid of patients with RA and are widely known to be involved with a variety of inflammatory disorders.^2,3 Abatacept is a selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CD86 on antigen-presenting cells. This action, in turn, prevents the interaction with CD28 on T-cells, resulting in lack of T-cell activation.

Clinical Trials

The AIM (Abatacept in Inadequate responders to Methotrexate) trial included ~650 patients who were inadequately controlled with MTX. The phase 3, double- blind, placebo-controlled study randomized patients to receive abatacept 10 mg/kg or placebo intravenously on days 1, 15, and 29 and every 28 days thereafter. Clinical responses were measured using American College of Rheumatology (ACR) improvement criteria and radiographs taken at the start and end of the study. At 3 months, there was significant improvement in participants' ACR components (ACR 20, 50, and 70), which also increased at months 6 and 12.³ Patients treated with abatacept demonstrated significant inhibition of joint damage, versus those taking a placebo (P = .012), in addition to fewer increases in joint damage (P < .001).⁴

ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders) was a phase 3 trial performed to evaluate efficacy and safety of abatacept in patients with active RA that is unresponsive to anti-TNF therapy. In this double-blinded, placebocontrolled study, patients were randomized to receive 10 mg/kg of abatacept or placebo on days 1, 15, and 29 and then every 28 days for 6 months thereafter.The primary end points of the trial were the proportion of patients with an ACR 20 response and those with an improvement of at least 0.3 from baseline in the Health Assessment Questionnaire (HAQ). After 6 months, the rate of ACR 20 response was 50.4% in the abatacept group, compared with 19.5% in the placebo group (P < .001). The rates of ACR 50 and 70 also were significantly improved in the abatacept group. The percentage of patients achieving an improvement on the HAQ of at least 0.3 from baseline was significantly higher in the abatacept group.⁵

Safety

Serious adverse events have included infections, exacerbations of chronic bronchitis, and malignancies. Other mild adverse events have included nausea and headache.² Giving abatacept with TNF antagonists is not recommended due to the increased risk of infections.² Patients with active infections or a history of recurrent infections should be monitored closely for signs of infection while on abatacept.

Pediatric safety or efficacy has not been established, and therefore abatacept should not be administered to children under 18 years of age.² A small number of geriatric patients were involved in clinical trials. They showed little difference in safety or efficacy, compared with nongeriatric patients, but extreme caution should be taken with the elderly due to their increased rates of infections and malignancies.²

Outlook

Orencia has been shown to be safe and effective in improving symptoms of RA and delaying disease progression in patients with mild-to-moderate disease. Orencia may be used with any other treatments for RA excluding TNF-alpha antagonists.²

Dr. Soo is a senior research pharmacist with the Investigational Drug Service at Brigham and Women's Hospital, Boston, Mass. Nolan Cook is a sixth-year PharmD candidate from Massachusetts College of Pharmacy currently on clinical clerkship in the Investigational Drug Service at Brigham and Women's Hospital.

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