Drug name: Humira (adalimumab)
Drug class: Tumor Necrosis Factor inhibitor
Manufacturer: AbbVie, Inc
Approval Date: December 31, 2002
Adalimumab is a tumor necrosis factor (TNF-alpha) inhibitor. Tumor necrosis factor inhibitors are antibodies that block the action of TNF made by the body. Tumor necrosis factor is a protein that is involved in triggering the inflammatory process and associated symptoms. Inhibiting TNF interferes with the inflammatory process, reducing inflammation, pain, swelling, tenderness of joints and other symptoms of inflammatory diseases. There are currently five drugs that target TNF-alpha:
Cimzia (certolizumab pegol)
History of Humira
Infliximab and Etanercept were the first FDA approved TNF-alpha inhibitors for rheumatoid arthritis treatment. About four years later adalimumab (D2E7) was developed by BASF Bioresearch Center and Cambridge Antibody Technologies. Adalimumab was developed as a fully human antibody to reduce immune system reactions caused by similar drugs that contain non-human DNA.
In the early 2000s, clinical trials showed promising results for adalimumab in the treatment of rheumatoid arthritis. Since infliximab is administered as an intravenous infusion and etanercept is a twice a week subcutaneous injection, adalimumab had an advantage due to its longer half life and administration once every two weeks. This is more convenient for patients.
Clinical trials data showed that adalimumab is as safe and effective as etanercept and infliximab for treatment of rheumatoid arthritis. With similar cost, a comparable safety and efficacy profile and better convenience in drug administration, adalimumab became a viable competitor to existing therapies. The FDA approval in 2002 for rheumatoid arthritis was followed by several more indications. Humira became the world’s top selling drug in 2012 with about 9.3 billion dollars of profit during that year. With Humira’s patent expiring in 2016, a new door of opportunities could open to new drug innovations and specifically the possibility of oral TNF inhibitors that could replace Humira’s place as number one in the market.
What is Humira’s Mechanism of Action
Adalimumab is a recombinant monoclonal antibody (man made protein) that binds to TNF-alpha and prevents it from binding to its receptor. This prevents inflammatory processes from occurring, reducing the symptoms and progression of inflammatory diseases such as arthritis, psoriasis, Crohn's disease, ulcerative colitis and ankylosing spondylitis.
What are Humira’s Indications
Moderate to severe rheumatoid arthritis
Moderate to severe polyarticular juvenile idiopathic arthritis in children
Psoriatic arthritis in adults
Ankylosing spondylitis in adults
Moderate to severe Crohn’s disease in adults
Moderate to severe chronic plaque psoriasis
Moderate to severe ulcerative colitis
Interesting Facts about Humira
Humira is the first fully human TNF-alpha inhibitor.
Humira is currently in phase 3 trials for HCV (Hepatitis C Virus) treatment.
Humira had $5.5 billion in sales during 2013, ranking number 3 in drug sales.
Humira’s Place in Therapy
Moderate to severe Rheumatoid Arthritis
Humira is FDA approved for reducing signs and symptoms, inhibiting structural damage, and reducing progression of moderate to severe rheumatoid Arthritis. Humira is a disease modifying anti-rheumatic drug (DMARD). A systematic review in 2008 of non-biologic and biologic DMARDs for the treatment of rheumatoid arthritis concluded that monotherapy with anti-TNF agents was as effective as methotrexate monotherapy. Combining methotrexate with an anti-TNF agent was more efficacious than monotherapy with either agent. Reduction in disease activity and slowing of radiographic progression were noted with combination therapy.
Ankylosing Spondylitis in adults
Humira is FDA approved for reducing the signs and symptoms of ankylosing spondylitis. The efficacy of Humira for treatment of ankylosing spondylitis was established in several clinical trials. Compared to placebo, Humira showed improvements in disease outcomes based on physicians and patient assessments. In addition, Humira showed a good safety profile and an improvement in patients’ quality of life.
Current guidelines recommend Humira for treatment of severe active ankylosing spondylitis. Studies have shown that patients with early stage ankylosing spondylitis exhibit a greater response than those with later stages of the disease.
Moderate to severe Crohn Disease
Adalimumab is FDA approved to reduce the signs and symptoms of Crohn's disease, and to induce and maintain remission in those who failed conventional therapy or infliximab. TNF-alpha therapy is initiated in patients who fail or do not tolerate glucocorticoids and or immunosuppressive drugs, or in those who have failed treatment with glucocorticoids and are unable to wait for the effects of methotrexate or azathioprine.
No randomized trials have compared the efficacy of different anti-TNF agents in the treatment of Crohn's Disease. Choosing an anti-TNF agent is based on availability and patient’s preference to use subcutaneous injections (e.g., adalimumab, certolizumab) versus intravenous administration (e.g., infliximab).
Chronic Plaque Psoriasis
Humira is FDA approved for the treatment of moderate to severe chronic plaque psoriasis in patients who qualify for systemic therapy or when other systemic medications are inappropriate to use. A randomized trial of 1212 patients with chronic plaque psoriasis evaluated the efficacy of Humira in treating chronic plaque psoriasis. Humira was more effective in treating moderate to severe chronic plaque psoriasis compared to placebo. After 16 weeks, 31% of patients in the Humira group had their disease cleared compared to 4% in the placebo group.
Moderate to severe polyarticular juvenile idiopathic arthritis in children (JIA)
Humira is FDA approved to reduce the signs and symptoms of JIA in children who are 4 years of age or older. A clinical trial of 171 patients with moderate to severe JIA evaluated Humira with or without methotrexate treatment. 37% of patients in the adalimumab and methotrexate group experienced a flare up compared to 65% in the placebo group. In the group that did not receive methotrexate, 43% experienced a flare up compared to 71% in the placebo group.
Moderate to severe Ulcerative Colitis
Humira is FDA approved to induce and maintain remission in patients with moderate to severe active ulcerative colitis who did not have an adequate response to immunosuppressants. The FDA approval was based on two clinical trials, ULTRA 1 and ULTRA 2. In both trials, Humira was more effective in inducing and maintaining remission than the placebo.
Adverse effects of Humira
The most common side effects associated with Humira are injection site reactions (8-20%), headache (12%), sinusitis (11%), upper respiratory infection (7%), and development of adalimumab antibodies.
The most serious side effects associated with Humira are congestive heart failure (<5%), Stevens-Johnson syndrome (<1%), infectious disease (>10%), agranulocytosis (<5%), tuberculosis (1-5%), malignancy (1-5%), lymphoma (1-5%), leukemia (<1%), anaphylaxis (<1%), hepatic failure (<1%), and deep vein thrombosis (1-5%).
Warnings and Precautions for Humira
Humira may cause hypersensitivity reactions including anaphylaxis. It may cause worsening or development of heart failure. Therefore, it should be used with caution in patients with a history of heart failure or those with diminished left ventricular function
Adalimumab lowers the ability of the immune system to fight infections and this may cause serious infections such as tuberculosis, bacterial, viral and fungal infections. These infections may lead to hospitalization and death. Humira also increases the chance of cancers such as lymphomas and skin cancer.
Humira's Drug Interactions
Combining Humira with other drugs that suppress the immune system increases the risk of serious infections
Combining tacrolimus, sirolimus, and cyclosporine with Humira results in decreased concentration of these drugs.
Giving live vaccines to people taking Humira results in a higher risk of secondary infection from the vaccine.
Cost of Humira
Humira is supplied as single use prefilled pen, glass syringe, and glass vial. The usual dose of Humira for rheumatoid arthritis is 40 mg every other week. The average wholesale price (AWP) for the 2 doses per month is $3,240.38.
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Rahim et al. (2014). Anti-tumor necrosis factor therapy in ulcerative colitis. UpToDate, Rutgeerts, P (Ed).