Pharmacology Update: Adalimumab—Humira
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA has approved a new anti-tumor necrosis factor alpha (TNF alpha) drug for the treatment of rheumatoid arthritis (RA). Adalimumab, produced by recombinant DNA technology using a mammalian cell system, is a monoclonal antibody (IgG1) specific for human TNF alpha. It is a fully human antibody compared to infliximab, which is a chimeric antibody (75% human and 25% mouse). Adalimumab, which is administered as a subcutaneous injection every other week, is marketed by Abbott as "Humira."
Indications
Adalimumab is indicated for reducing the signs and symptoms and inhibiting the progression of structural damage in adults with moderately to severely active RA who have not adequately responded to one or more disease-modifying antirheumatic drugs (DMARDs). In may be used alone or in combination with methotrexate or other DMARDs.1
Dosage
The recommended dose is 40 mg given subcutaneously every other week. For those not taking methotrexate, dosing every week may be needed to achieve optimal effect.1
Adalimumab is supplied as a single-use prefilled syringe or single-use vial for patient or institutional use. The product should be refrigerated but not frozen.1
Potential Advantages
Adalimumab has been shown to inhibit the progression of structural damage in adults with moderately severely active RA with inadequate response to methotrexate. This study (n = 407) was assessed radiographically at 1 year and was expressed as change in erosion, joint space narrowing, and total score (erosion plus narrowing).1 Significant differences were detected between patients on adalimumab and methotrexate compared to methotrexate and placebo. In a small, open label study of adalimumab monotherapy (n = 36), 42% showed no radiographic progression.2 Adalimumab is given by subcutaneous injection every 2 weeks compared to twice weekly subcutaneous injections for etanercept and every 8-week intravenous infusions for infliximab.
Potential Disadvantages
The drug may affect the host defense against infections and malignancies. Active tuberculosis has been associated with TNF-alpha therapy including adalimumab.1,5 Patients should be tested for latent tuberculosis and treated if needed before initiating anti-TNF therapy. A higher incidence of lymphomas and development of autoantibodies have also been observed. Forty-eight cases of malignancies and 10 cases of lymphoma were observed in 2468 patients treated with adalimumab for a median of 24 months. In controlled trials, 17% of patients developed antinuclear antibodies (ANA) compared to 7% of placebo-treated patients. One patient (out of 2334) developed lupus-like syndrome.1 Adalimumab should be prescribed with caution in patients with preexisting or recent-onset CNS demyelinating disorders. Neutralizing antibody formation was more common with monotherapy (12%) than in combination with methotrexate (1%). The rate was also higher with every other week therapy compared with weekly therapy. Efficacy was lower in patients with neutralizing antibodies.1 Injection site reaction (20%) is the most common side effect.
Comments
Adalimumab is a fully human monoclonal antibody with high and specific affinity for TNF-alpha thus preventing binding to its receptors. TNF-alpha is a proinflammatory cytokine believed to play an essential role in articular matrix degradation and progression of inflammatory synovitis.3,4 Adalimumab produces a rapid decrease in acute phase reactants of inflammation (eg, C-reactive protein and erythrocyte sedimentation rate) and modulates cartilage and synovium turnover as measured by biological markers (eg, metalloproteinase, cartilage oligomeric matrix protein).1,2,6 The efficacy and safety of adalimumab was assessed in 4 randomized, double-blind studies in adult RA patients. Efficacy was based on American College of Rheumatology (ACR20, ACR50, or ACR70). This represents a 20%, 50%, or 70% improvement in patient’s tender joint count and swollen joint count plus the same percentage improvement or greater in at least 3 of the following criteria: 1) patient’s pain assessment; 2) patient’s global assessment; 3) physician’s global assessment; 4) patient’s self-assessed disability; and 5) acute-phase reactant (ESR or CRP). In placebo-controlled trials, ACR20 was 46% (vs 19%) for monotherapy at 6 months and 63% (vs 30%) and 59% (vs 34%) for combined therapy with methotrexate at 6 and 12 months, respectively.1 These are similar to those reported for etanercept and infliximab.4 Radiographic evaluation of disease progression was an additional primary end point in one of the randomized trial. This study demonstrated that patients who received adalimumab/methotrexate had less joint deterioration than those who received methotrexate alone. The effect of inhibition of TNF-alpha is an ongoing concern. Opportunistic infections, malignancies, autoantibodies, and demyelinating disease have been associated with anti-TNF-alpha therapy. The wholesale cost of adalimumab is about $1300 per month, which is similar to that of etanercept.
Clinical Implications
Adalimumab is the latest of the TNF-alpha inhibitors joining infliximab (chimeric monoclonal antibody) and etanercept (a soluble receptor). There are currently no published comparative trials among these agents. Efficacy as assessed by ACR criteria across studies appears to be similar among the 3 drugs. Whether there are true differences in efficacy (ACR and/or disease progression) and/or side effects remain to be determined.
Dr. Elliott is Chair of the Formulary Committee, Northern California Kaiser Permanente and Assistant Clinical Professor of Medicine at the University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager at Kaiser Permanente in Oakland, CA.
References
1. Humira Product Information. Abbott Laboratories. December 2002.
2. den Broeder A, et al. Ann Rheum Dis. 2002;61(4):311-318.
3. Choy EH, Panayi GS. N Engl J Med. 2001;344: 907-916.
4. Rau R. Ann Rheum Dis. 2002;61(Suppl 2):ii70-ii73.
5. Criscione LG, St. Clair EW. Curr Opin Rheumatol. 2002;14:204-211.
6. Furst D, et al. Arthritis Rheum. 2001;9(suppl):S215.
The FDA has approved a new anti-tumor necrosis factor alpha (TNF alpha) drug for the treatment of rheumatoid arthritis (RA).
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content