Abbott today announced that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMEA), granted a positive opinion recommending approval of HUMIRA(R) (adalimumab) for the treatment of severe active ankylosing spondylitis. The positive opinion is based on results from the Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS) Phase III clinical trial. In October 2005, Abbott submitted a supplemental Biologics License Application (sBLA) with the U.S. Food and Drug Administration (FDA) seeking approval to market HUMIRA as a treatment for AS.
Ankylosing spondylitis (AS) is a chronic disease of the axial skeleton and large peripheral joints that causes inflammatory back pain and stiffness but is also associated with other inflammatory diseases of the skin and intestines. Unlike many other rheumatic conditions, AS affects young adults, mostly men, and commonly begins before the age of 35. AS is difficult to diagnose in its early stages and often is an overlooked cause of persistent back pain in young adults. In its severe form, AS over time can result in complete spinal fusion, causing extreme physical limitation. It is estimated that nearly three million people in Europe are affected by a spondyloarthritis, such as AS.
“The positive opinion is encouraging news for European ankylosing spondylitis patients because it signals that a new treatment option will soon be available to address the symptoms of the disease,” said Desiree van der Heijde, M.D., co-lead investigator of ATLAS and Professor of Rheumatology at the Maastricht University, The Netherlands.
The European Commission is expected to issue a decision granting the marketing authorization for HUMIRA as a treatment of AS in the European Union within approximately 60 days.
Highlights of the ATLAS Study
Ankylosing spondylitis patients (n = 315), who had an inadequate response to at least one nonsteroidal anti-inflammatory drug (NSAID) or disease- modifying antirheumatic drug (DMARD), were randomized to receive either placebo or HUMIRA 40 mg subcutaneously every other week for 24 weeks. Results recorded after 12 weeks and 24 weeks of treatment showed that HUMIRA significantly reduced signs and symptoms (the study’s primary endpoint), including pain and inflammation, in patients with severe active AS. Findings also indicated HUMIRA reduced disease activity, induced partial remission, improved physical function and improved physical quality of life.
ATLAS study data showed that 58 percent of the trial participants receiving HUMIRA therapy achieved and sustained at least a 20 percent reduction in signs and symptoms of pain and inflammation at 12 weeks (ASAS 20, one of the study’s primary endpoints). Responses were measured using the ASsessment in AS (ASAS) International Working Group criteria, which evaluate four primary parameters: function, pain, patient’s global assessment, and inflammation.
At week 24, 42 percent of patients treated with HUMIRA, compared to 16 percent of patients taking placebo, achieved at least a 50 percent reduction of disease activity as measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), a patient-assessed composite index of disease activity measuring pain, stiffness and fatigue. Also at week 24, approximately one out of five patients achieved partial remission (defined as a value <20 on a 0-100 scale in each of the four ASAS domains).
ATLAS also explored the impact of HUMIRA on enthesitis, a primary pathology in AS characterized by inflammation of the ligaments that attach to the bone. At week 24, mean change in the enthesitis symptom score as measured by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in patients treated with HUMIRA showed a 50 percent reduction. MASES is an index that assesses enthesitis in certain domains, such as costochondral joint (relating to or joining a rib and costal cartilage), iliac spine and Achilles tendons.
“Patients with rheumatoid arthritis and psoriatic arthritis already benefit from HUMIRA,” said Rebecca Hoffman, M.D., divisional vice president, Immunology Development, Abbott. “With these two indications, and now with the promise shown in ankylosing spondylitis, HUMIRA continues to reaffirm its potential as a therapy to treat multiple autoimmune diseases.”
A similar rate of treatment emergent adverse events leading to discontinuation of study drug was observed among placebo treated (1.9%) and HUMIRA treated (1.4%) patients. The overall incidence of adverse events reported by patients treated with HUMIRA was higher than the placebo treatment patients. The most common adverse events included nasopharyngitis, injection site reactions and headache.
About Ankylosing Spondylitis
Ankylosing spondylitis, or arthritis of the spine, is an autoimmune disorder in which a human protein, tumor necrosis factor-alpha, has been suggested to play a role in the disease development. AS is a form of arthritis known as spondyloarthritis, which is a group of closely linked rheumatic diseases that can cause pain in the spine and joints as well as ligaments and tendons, and also can cause inflammation that predisposes patients to spinal vertebrae fractures. AS is a chronic disease that primarily affects the spine by causing back stiffness and the potential for deformity over time. AS is associated with a number of extra-axial manifestations including peripheral arthritis and enthesitis. Other associated affected organ systems may include the eyes, intestines and skin.
Important Safety Information
Common adverse events (>1/100 and <1/10) at least possibly causally related to HUMIRA include lower respiratory infections (including pneumonia, bronchitis), urinary tract infection, herpetic viral infection (including simplex and zoster), influenza, superficial fungal infections (including skin, nail and foot), lymphopenia, anemia, headache, dizziness, paraesthesias, hypertension, cough, nasopharyngeal pain, nasal congestion, nausea, abdominal pain, diarrhea, dyspepsia, mouth ulceration, rash erythematous, rash pruritic, hair loss, arthritis, fatigue (including asthenia and malaise), influenza like illness, hepatic enzymes increased (including alanine aminotransferase and aspartate aminotransferase), rash, pruritis and injection site reaction (including pain, swelling, redness or pruritus) and upper respiratory infection was reported by >1/10 patients.
Patients must be monitored closely for infections, including tuberculosis (TB), before, during and after treatment with HUMIRA. Treatment should not be initiated in patients with active infections until infections are controlled. Patients who develop new infections while using HUMIRA should be monitored closely. HUMIRA should not be used by patients with active TB or other severe infections such as sepsis and opportunistic infections. HUMIRA should be discontinued if a patient develops a new serious infection until infections are controlled. Physicians should exercise caution when considering use of HUMIRA in patients with a history of recurring infection or with underlying conditions that may predispose patients to infections.
TNF antagonists, including HUMIRA, have been associated in rare cases with exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease. Prescribers should exercise caution in considering the use of HUMIRA in patients with pre-existing or recent-onset central nervous system demyelinating disorders.
Physicians should exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully. In clinical studies with another TNF antagonist, a higher rate of serious congestive heart failure (CHF) related adverse events including worsening CHF and new onset CHF have been reported. Cases of worsening CHF have also been reported in patients receiving HUMIRA.
HUMIRA, in combination with methotrexate, is indicated for the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying antirheumatic drugs including methotrexate has been inadequate as well as for the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.
HUMIRA can be given as monotherapy in case of intolerance to methotrexate or when continued treatment of methotrexate is inappropriate. HUMIRA has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with methotrexate.
HUMIRA is indicated for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying antirheumatic drug therapy has been inadequate.
To date, HUMIRA has been approved in 65 countries and prescribed to more than 150,000 patients worldwide. Clinical trials are currently underway evaluating the potential of HUMIRA in other autoimmune diseases.
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