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General Information

Humira (adalimumab) is a recombinant human IgG1 monoclonal antibody indicated for reducing signs and symptoms and inhibiting the progression of structural damage in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more DMARDs. Humira is supplied in single-use, 1 mL pre-filled glass syringes, and also 2 mL glass vials as a sterile, preservative-free solution for subcutaneous administration.

The recommended dose of Humira for adult patients with rheumatoid arthritis is 40 mg administered every other week as a subcutaneous injection.

The FDA approved Humira on December 31, 2002, nine months after simultaneous regulatory submissions in the United States and Europe.

Clinical Results

The efficacy and safety of Humira were assessed in four randomized, double blind studies in Subjects with active rheumatoid arthritis. Humira was administered subcutaneously in combination with MTX or as monotherapy or with other disease modifying anti-rheumatic drugs.

Study I evaluated 271 subjects whom had failed therapy with at least one but no more than four DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of Humira or placebo were given every other week for 24 weeks.

Study II evaluated 544 Subjects who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of Humira were given as monotherapy every other week or weekly for 26 weeks.

Study III evaluated 619 Subjects who had an inadequate response to MTX. Subjects received placebo, 40 mg of Humira every other week with placebo injections on alternate weeks, or 20 mg of Humira weekly for up to 52 weeks. Study III had an additional primary endpoint at 52 weeks of inhibition of disease progression.

Study IV assessed safety in 636 Subjects who were either DMARD-naive or were permitted to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Subjects were randomized to 40 mg of Humira or placebo every other week for 24 weeks.

In all four studies, Humira showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire from baseline to the end of study, and significantly greater improvement than placebo in the health-outcomes as assessed by The Short Form Health Survey. Improvement was seen in both the Physical Component Summary and the Mental Component Summary.

Side Effects

Adverse events associated with the use of Humira may include (but are not limited to) the following:

Upper respiratory infection
Sinusitis
Flu syndrome
Nausea
Abdominal pain

Mechanism of Action

Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis patients and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of rheumatoid arthritis.

Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M).

Literature References

1. Arnett FC, Edworthy SM, Bloch DA, et. al. The American Rheumatology Association 1987 Revised Criteria for the Classification of Rheumatoid Arthritis. Arthritis Rheum 1988; 31:315-24.

2. Ramey DR, Fries JF, Singh G. The Health Assessment Questionnaire 1995 -Status and Review. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. Philadelphia, PA. Lippincott-Raven 1996.

3. Ware JE, Gandek B. Overview of the SF-36 Health Survey and the International Quality of Life Assessment (IQOLA) Project. J Clin Epidemiol 1998; 51(11):903-12.

4. Mellemkjaer L, Linet MS, Gridley G, et al. Rheumatiod Arthritis and Cancer Risk. European Journal of Cancer 1996; 32A (10): 1753-1757.

5. Baecklund E, Ekbom A, Sparen P, et al. Disease Activity and Risk of Lymphoma in Patients With Rheumatoid Arthritis: Nested Case-Control Study. BMJ 1998;317: 180-181.

6. Centers for Disease Control and Prevention. Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection. MMWR 2000; 49(No. RR-6):26-38.