The combination of Abbott Laboratories' Humira (adalimumab) with methotrexate in patients with active, long-standing rheumatoid arthritis (RA) resulted in significantly less structural joint damage and improved physical function and health-related quality of life at 52 weeks, according to data published in the May issue of Arthritis and Rheumatism. In the study, some Humira patients responded to treatment as soon as two weeks after their initial dose, as measured by signs and symptoms of RA.

"Newer treatments such as Humira represent a giant step forward from older therapies in their ability to slow or even halt joint destruction and allow patients to return to a more normal lifestyle," said Edward C. Keystone, M.D., study author, University of Toronto, Canada. "In this study, Humira combined with methotrexate offered significant and sustained radiographic, clinical and quality of life advantages compared to methotrexate alone for patients with long-standing disease who had an inadequate response to methotrexate."

This study was a pivotal trial that supported the U.S. and European approval of Humira. The trial was designed to evaluate radiographic outcomes as well as the clinical efficacy and safety of Humira over a 52-week period. The study evaluated patients with active RA who had average disease duration of more than 10 years, and who had inadequate response to methotrexate (MTX), a commonly used disease modifying anti-rheumatic drug (DMARD). The data are from 619 patients who received Humira 40 mg every other week, Humira 20 mg weekly or placebo. All patients received stable doses of MTX.

At weeks 24 and 52, Humira-treated patients had significantly less disease progression than placebo-treated patients, according to modified Sharp and erosion scores.

Patients taking Humira 40 mg every other week plus MTX experienced significantly less radiographic progression, as measured by a change in mean total Sharp score of 0.1 vs. 2.7 for patients on placebo plus MTX. Modified total Sharp scores assess changes in bone erosion and joint-space narrowing on X-rays: i.e., a lower change in total Sharp score indicates less disease progression.

At week 52, no new erosions were observed in significantly more patients receiving Humira 40 mg every other week (61.8 percent) than in those taking placebo (46 per cent). Also, joint-erosion scores improved in almost twice as many patients receiving Humira 40 mg every other week than placebo, (38.2 per cent vs. 19.3 per cent, respectively).

Patients receiving Humira also reported significant improvements in clinical manifestations of the disease such as swollen and tender joint counts and pain. The ability of Humira to reduce the signs and symptoms of RA was measured using the American College of Rheumatology (ACR) 20, 50 and 70 criteria, which represent percent improvement in tender and swollen joint counts and other relevant clinical measures.

Humira patients demonstrated rapid, statistically significant and sustained improvements in signs and symptoms of their disease versus those on placebo. At 52 weeks, nearly one in four (23.2 per cent) patients treated with Humira 40 mg every other week achieved an ACR 70 score, which represents the closest clinical measure to remission, compared to 4.5 per cent in the placebo group.

ACR 20 responses were achieved by 59 per cent of patients receiving Humira 40 mg every other week compared to placebo (24 per cent), and ACR 50 responses were achieved by 41.5 per cent vs. placebo (9.5 per cent).

"These data are particularly important because RA is a progressive, life-long disease, and Humira offers patients a treatment option with proven capacity to slow joint destruction and reduce signs and symptoms," said James B. Lefkowith, M.D., divisional vice president, development, Abbott Immunology.

The study also examined the impact of Humira on patients' physical function and health-related quality of life (QOL). Physical function was measured by the Health Assessment Questionnaire (HAQ) disability index. Health-related QOL was measured by the Medical Outcomes Study 36-item Short Form Health Survey (SF-36). The HAQ disability index is designed to capture patients' assessment of activities of daily living, such as grooming, dressing and walking. The SF-36 is a questionnaire that measures patients' assessment of general QOL measures.

Improvement in physical functioning, as determined by HAQ, was significantly greater for Humira patients on 40 mg every other week (-0.59) than for patients on placebo (-0.25) at week 52. A 0.22-unit decrease in HAQ scores has been associated with meaningful clinical improvements.

At week 52, patients on Humira 40 mg every other week achieved at least a 10-point improvement in five key SF-36 domains: physical function, physical role, bodily pain, vitality and social function. Increases of five to 10 points in individual SF-36 domain scores have been associated with meaningful clinical improvements.

In this study, the rate of adverse events was similar among patients treated with Humira and placebo, although the proportion of patients reporting serious infections was higher in patients receiving Humira (3.8 per cent) than placebo (0.5 per cent). The most common adverse events included injection-site reaction (26.1 per cent vs. 24 per cent, Humira 40 mg every other week plus MTX vs. placebo plus MTX), upper-respiratory infection (19.8 per cent vs. 13.5 per cent), rhinitis (16.4 per cent, vs. 16.5 per cent) and sinusitis (15.9 per cent vs. 13 per cent). Forty-two Humira patients and 13 placebo patients withdrew from the study due to adverse events.

Cases of tuberculosis (TB), frequently disseminated or extra pulmonary at clinical presentation, have been observed in patients receiving Humira. Serious infections and sepsis, including fatalities, have been reported with the use of TNF-blocking agents, including Humira. Many of these infections occurred in patients on concomitant immunosuppressive therapy that in addition to their underlying disease could predispose them to infections. Other invasive opportunistic fungal infections have also been observed in patients treated with TNF-blocking agents, including Humira.

TNF-blocking agents, including Humira, have been associated in rare cases with exacerbation of demyelinating disease. Lymphoma has been observed in patients treated with TNF-blocking agents. The most frequent adverse events seen in the placebo-controlled clinical trials (Humira vs. placebo) were injection site reactions (20 per cent vs. 14 per cent), upper respiratory infection (17 per cent vs. 13 per cent), injection site pain (12 per cent vs. 12 per cent), headache (12 per cent vs. 8 per cent), rash (12 per cent vs. 6 per cent) and sinusitis (11 per cent vs. 9 per cent). Discontinuations due to adverse events were 7 per cent for Humira and 4 per cent for placebo. As with any treatment program, the benefits and risks of Humira should be carefully considered before initiating therapy.

Humira is the first fully human monoclonal antibody approved by the FDA for reducing the signs and symptoms and inhibiting the progression of structural damage in adults with moderately to severely active RA who have had an inadequate response to one or more DMARDs. Humira can be used alone or in combination with MTX or other DMARDs.

Humira is a recombinant human IgG1 monoclonal antibody specific for human TNF. Humira was created using phage display technology, resulting in an antibody with human-derived heavy and light chain variable regions and human IgG1:K constant regions.

On September 10, 2003, Abbott announced that the European Commission granted marketing authorization to Humira for the treatment of adult RA. With E.U. marketing authorization, Humira became the first fully human monoclonal antibody approved in Europe for RA and the first tumor necrosis factor alpha (TNF-a) antagonist approved with an indication for use with MTX or as monotherapy. Humira is indicated for the treatment of moderate to severe active RA in adult patients when the response to DMARDs, including methotrexate, has been inadequate. To date, Humira has been approved in 41 countries and launched in 26 (including the United States).

Clinical trials are currently underway evaluating the potential of Humira in other autoimmune diseases.

Humira was discovered through a broad scientific collaboration between Abbott and Cambridge Antibody Technology (CAT). As part of the collaboration, Abbott had the right to select several target antigens for which a joint Abbott/CAT research team would discover human antibody therapeutics. Humira was isolated and optimized by Abbott and CAT as part of this collaboration. Abbott owns exclusive worldwide rights to Humira, including responsibility for clinical development, manufacturing, sales and marketing. Abbott will book all revenues for Humira, and CAT will receive a royalty fee based on Humira sales.