The TEMPO extension trial was an open-label 52 week study involving subjects who had completed the 3-year double-blind TEMPO trial. At the end of the 3-year TEMPO trial, 227 subjects who met the specific predefined criteria continued into the 1-year, open-label extension. All subjects received treatment with the combination of ENBREL and methotrexate. Subjects receiving methotrexate monotherapy during the 3-year double-blind TEMPO trial were switched to the combination of ENBREL and methotrexate (n = 55). Subjects receiving ENBREL monotherapy during the 3-year double-blind TEMPO trial were switched to the combination of ENBREL and methotrexate (n = 76). Subjects receiving combination therapy during the 3-year double-blind TEMPO trial were continued on the same regimen (n = 96).
Commenting on the implications of the results, study investigator Dr Emilio Martín Mola, chief of the rheumatology department, Hospital Universitario de La Paz in Madrid and professor, Universidad Autónoma de Madrid, Spain said: "Patients with rheumatoid arthritis, who have active disease after an adequate regimen of methotrexate, can improve significantly when etanercept is added. Whether newly diagnosed patients with active rheumatoid arthritis should be put on this combination regimen is a matter for discussion, but it is a good therapeutic strategy for those patients with aggressive, rheumatoid arthritis."
Heather Widnall, UK, who has rheumatoid arthritis and took the combination of ENBREL and methotrexate for four years said, "Before I started taking ENBREL and methotrexate, my joints were painful and swollen; I found it difficult to walk, grip things, get dressed in the morning and generally live my life. Over the last four years of treatment, my quality of life has improved, and I experience less disability."1
The results of the 227 patient one-year open-label extension of the TEMPO study showed that the combination therapy with ENBREL and methotrexate demonstrated clinical improvement and was generally well-tolerated during the one-year study.1 Fifty per cent of patients taking ENBREL and methotrexate for four years achieved clinical remission based on the disease activity score (DAS) of less than 1.6, the primary clinical efficacy endpoint, compared with 38.7 per cent at three years.1 Seventy-four per cent of patients taking ENBREL and methotrexate for four years achieved a DAS of less than 2.4 (low disease activity) compared with 66.7 per cent at three years.1 DAS is a combined index to measure disease activity in rheumatoid arthritis patients and is a validated tool used in clinical trials and serves as the basis for the EULAR response criteria. In addition, the data also demonstrate that among the rheumatoid arthritis patients treated with methotrexate monotherapy for three years, whose mean disease activity was moderate, the addition of ENBREL provided further improvement in clinical efficacy that approached the response achieved by patients treated with combination therapy for four years (mean DAS 1.9 vs. 1.8, respectively).1 The addition of methotrexate to patients who received ENBREL monotherapy for three years also resulted in improvements at four years (mean DAS 2.2)1. The proportions of subjects achieving clinical remission by adding ENBREL to methotrexate and adding methotrexate to ENBREL at four years were 41.8% and 38.2% and were not statistically different from each other nor compared to the combination group.
Ailsa Bosworth, chief executive, National Rheumatoid Arthritis Society, UK said, "Rheumatoid arthritis is a painful and debilitating disease that has consequences not only for people with the condition but also for their families, friends and employers. It is vital that people with rheumatoid arthritis have access to treatments that have been proven effective to inhibit the progression of joint damage and to improve physical function."
Stevo Knezevic, MD, PhD, chief medical officer of Wyeth Europe commented, "These results clearly show rheumatoid arthritis patients on methotrexate or ENBREL monotherapy may benefit from treatment with the combination of ENBREL and methotrexate. It is important that health care providers make these therapies available as quickly as possible for appropriate patients."
Rheumatoid arthritis affects approximately 0.5 to one per cent of the adult population worldwide, and about twice as many women as men suffer from the disease.2 It is a frequently progressive, destructive, chronic, systemic autoimmune disease of unknown aetiology.3 Patients with rheumatoid arthritis experience pain, inflammation, and morning stiffness, usually in the small joints of the hands and feet and often symmetrically. As the disease progresses, irreversible joint damage may lead to loss of function and physical disability. Rheumatoid arthritis can be a devastating disease that can negatively affect quality of life and may result in increased feelings of depression. During the first two to three years of the disease, 20 to 30 per cent of patients become permanently work disabled. Within 10 years of onset, at least 50 per cent of patients are unable to work. Because rheumatoid arthritis is a systemic disease, it can also lead to pulmonary, ocular, and cardiac complications.3
In the European Union, ENBREL is approved alone or in combination with methotrexate for the treatment of active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate. ENBREL is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. In patients with rheumatoid arthritis, ENBREL used alone or in combination with methotrexate has been shown to slow the progression of disease-associated structural damage as measured by X-ray.
ENBREL is given by injection and the recommended dosing is 50 mg once weekly for all adult rheumatology indications.
Since the product was first introduced, serious infections, some involving death, have been reported in patients using ENBREL. Patients should tell their doctor if they currently have an infection or are prone to getting infections. Patients should not start ENBREL if they have an infection of any type or an allergy to ENBREL or its components. ENBREL should be used with caution in patients prone to infection.
There have been reports of serious nervous-system disorders such as multiple sclerosis and/or inflammation of the nerves of the eyes. Patients should inform their doctor if they have ever had any of these disorders or if they develop them after starting ENBREL.8 Patients should also tell their doctor if they have ever been treated for heart failure. There also have been rare reports of serious blood disorders, some involving death.
Patients should contact their doctor immediately if they develop symptoms such as persistent fever, bruising, bleeding, or paleness. It is unclear if ENBREL has caused these nervous-system or blood disorders. If a patient's doctor confirms serious blood problems, patients may need to stop using ENBREL.
The most frequent adverse events in clinical trials in rheumatoid arthritis patients were injection-site reactions (ISRs) (36%), infections (35%), and headaches (17%) Malignancies were rare.
Physicians in Europe have become familiar with the benefits and long-term tolerability profile of ENBREL since it became commercially available over six years ago. More than 400,000 patients have been treated worldwide across indications. ENBREL acts by binding tumor necrosis factor (TNF), one of the dominant inflammatory cytokines or regulatory proteins that play an important role in both normal immune function and the cascade of reactions that causes the inflammatory processes of rheumatoid arthritis. The binding of ENBREL to TNF renders the bound TNF biologically inactive, which can result in significant reduction in inflammatory activity.
Wyeth Pharmaceuticals, a division of Wyeth, has leading products in the areas of women's health care, cardiovascular disease, central nervous system, inflammation, transplantation, hemophilia, oncology, vaccines and nutritional products. Wyeth is one of the world's largest research-driven pharmaceutical and health care products companies. It is a leader in the discovery, development, manufacturing, and marketing of pharmaceuticals, vaccines, biotechnology products and nonprescription medicines that improve the quality of life for people worldwide. The Company's major divisions include Wyeth Pharmaceuticals, Wyeth Consumer Healthcare, and Fort Dodge Animal Health. Wyeth Pharmaceuticals markets ENBREL outside North America. ENBREL was discovered by Immunex, now part of Amgen (NASDAQ: AMGN), and jointly developed with Wyeth Pharmaceuticals. The two companies co-promote ENBREL in North America.
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1. CSR-64179 An open-label, multicentre, extension study of the combination of etanercept and methotrexate in rheumatoid arthritis subjects. 11 May 2006
2. Gabriel SE. The epidemiology of rheumatoid arthritis. Rheum. Dis. Clin. North Am. 2001;27:269-281
3. Harris ED Jr. Rheumatoid arthritis: pathophysiology and implications for therapy. N Engl J Med. 1990;322:1277-1289
4. Fuchs HA, Sergent JS. Rheumatoid arthritis: the clinical picture. In: Koopman WJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology. 13th ed. Baltimore, Md: Williams & Wilkins: 1997;1:1041-1065
5. Schned ES, Reinertsen JL. The social and economic consequences of rheumatic disease. In: Klippel JH, ed. Primer on Rheumatic Diseases. 11th ed. Atlanta, Ga: Arthritis Foundation; 1997:6-9
6. Sokka T. Work disability in early rheumatoid arthritis. Clin Exp Rheumatol. 2003 Sep-Oct;21(5 Suppl 31):S71-4.
7. Yelin E, Henke C, Epstein W. The work dynamics of the person with rheumatoid arthritis. Arthritis Rheum. 1987 May;30(5):507-12.
8. Gladman DD et al, Psoriatic arthritis (PsA) – An analysis of 220 patients. Quarterly Journal of Medicine. New series 62, No. 238 pp. 127-141, February 1987
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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