Abbott seeks U.S. and E.U. approvals for Humira as a treatment for juvenile rheumatoid arthritis

Abbott has announced it has simultaneously submitted a supplemental Biologics License Application (sBLA) with the U.S. Food and Drug Administration (FDA) and a Type II Variation to the European Medicines Agency (EMEA) seeking approval to market HUMIRA (adalimumab) as a treatment for juvenile rheumatoid arthritis (JRA) in the U.S. and juvenile idiopathic arthritis (JIA) in the European Union (EU).

This filing marks the first pediatric indication sought for HUMIRA.

JRA, commonly referred to as JIA in the EU, is the most common form of arthritis in children and normally begins before the age of 16. Typical symptoms include persistent joint pain and stiffness that are usually worse in the morning or after a nap. The pain may limit movement of the affected joint, although many children will not complain of the pain. Walking with a limp is an early sign of JRA due to an affected knee. Depending on the severity of disease, JRA may affect bone development or cause growth abnormalities, such as one leg or arm growing longer than the other. The goal of treatment for JRA is to control inflammation, relieve pain, and preserve mobility and joint function, and ultimately prevent disease progression.

"If left untreated, JRA may slow a child's growth and cause disability into adulthood," said Daniel J. Lovell, MD, MPH, associate director, Special Treatment Center for Juvenile Arthritis, Cincinnati Children's Hospital Medical Center, Cincinnati. "HUMIRA may offer hope to children suffering with this unpredictable disease."

The global filing is based on the results of a Phase III, 48-week study that included 171 children (4 to 17 years old) with polyarticular JRA, a form of arthritis affecting five or more joints, usually the same joints on both sides of the body. Additional data will be submitted from an ongoing open label extension study evaluating the long-term efficacy and safety of HUMIRA.

In the first part of the study, two groups of patients -- those taking methotrexate (MTX) and not taking MTX -- received HUMIRA subcutaneously every other week (EOW) for 16 weeks. Patient responses were measured using the American College of Rheumatology (ACR) Pediatric 30 score, which represents a 30 percent improvement in JRA signs and symptoms, such as the number of swollen joints with loss of motion, assessment of pain and level of disability. Children who showed a positive clinical response (n=133) entered the second part of the study and were randomized to receive HUMIRA or placebo for an additional 32 weeks or until disease flare. A flare was defined as a worsening of 30 percent or more in three of the six ACR Ped response variables, a minimum of two active joints, and no more than one indicator improving by 30 percent.

Children receiving HUMIRA, in the second part of the study, had significantly fewer disease flares than children on placebo, both without MTX (43 percent vs. 71 percent) and with MTX (37 percent vs. 65 percent). Additionally, twice as many children on HUMIRA achieved ACR Ped 70 compared to those on placebo (56 percent vs. 28 percent, respectively) at Week 48. The most common adverse events were infections (mostly mild upper respiratory) and injection site reactions. No tuberculosis or opportunistic infections were reported during this study. The adverse events observed in children were similar to those observed in adults in previous rheumatoid arthritis (RA) studies with HUMIRA.

HUMIRA is approved to treat adult patients with moderately to severely active rheumatoid arthritis. More than 180,000 patients worldwide are currently being treated with HUMIRA. HUMIRA is currently being studied in pediatric Crohn's disease, and Abbott plans to initiate trials for pediatric and adolescent psoriasis later this year.

"We are pleased by the submission of our first pediatric indication for HUMIRA," said Eugene Sun, M.D., vice president, Global Pharmaceutical Clinical Development at Abbott. "HUMIRA has already benefited thousands of adults suffering with RA, and this trial shows promise for children and families who are impacted by JRA."

Globally, prescribing information varies; refer to the individual country product label for complete information.

Serious infections, sepsis, tuberculosis (TB) and opportunistic infections, including fatalities, have been reported with the use of TNF- blocking agents, including HUMIRA. Many of these serious infections have occurred in patients also taking other immunosuppressive agents that in addition to their underlying disease could predispose them to infections. Infections have also been reported in patients receiving HUMIRA alone. Treatment with HUMIRA should not be initiated in patients with active infections. TNF-blocking agents, including HUMIRA, have been associated with reactivation of hepatitis B (HBV) in patients who are chronic carriers of this virus. Some cases have been fatal. Patients at risk for HBV infections should be evaluated for prior evidence of HBV infections before initiating HUMIRA. The combination of HUMIRA and anakinra is not recommended and patients using HUMIRA should not receive live vaccines.

More cases of malignancies have been observed among patients receiving TNF blockers, including HUMIRA, compared to control patients in clinical trials. These malignancies, other than lymphoma and non-melanoma skin cancer, were similar in type and number to what would be expected in the general population. There was an approximately 3.5 fold higher rate of lymphoma in combined controlled and uncontrolled open-label portions of HUMIRA clinical trials. The potential role of TNF-blocking therapy in the development of malignancies is not known. TNF-blocking agents, including HUMIRA, have been associated in rare cases with demyelinating disease and severe allergic reactions. Infrequent reports of serious blood disorders have been reported with TNF-blocking agents.

Worsening congestive heart failure (CHF) has been observed with TNF- blocking agents, including HUMIRA, and new onset CHF has been reported with TNF-blocking agents. Treatment with HUMIRA may result in the formation of autoantibodies and rarely, in development of a lupus-like syndrome.

The most frequent adverse events seen in the placebo-controlled clinical trials in adults with rheumatoid arthritis (HUMIRA vs. placebo) were injection site reactions (20 percent vs. 14 percent), upper respiratory infection (17 percent vs. 13 percent), injection site pain (12 percent vs. 12 percent), headache (12 percent vs. 8 percent), rash (12 percent vs. 6 percent) and sinusitis (11 percent vs. 9 percent). Discontinuations due to adverse events were 7 percent for HUMIRA and 4 percent for placebo. As with any treatment program, the benefits and risks of HUMIRA should be carefully considered before initiating therapy.

In HUMIRA clinical trials for ankylosing spondylitis, psoriatic arthritis and Crohn's disease, the safety profile for adult patients treated with HUMIRA was similar to the safety profile seen in adult patients with rheumatoid arthritis.

HUMIRA is the only fully human monoclonal antibody approved for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) in the U.S. and Europe and Crohn's disease in the U.S. HUMIRA resembles antibodies normally found in the body. It works by blocking tumor necrosis factor alpha (TNF-alpha), a protein that when produced in excess, plays a central role in the inflammatory responses of many immune- mediated diseases. Clinical trials are currently under way evaluating the potential of HUMIRA in other autoimmune diseases.

In the U.S., HUMIRA is approved by the FDA for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of joint structural damage, and improving physical function in adult patients with moderately to severely active RA. HUMIRA is indicated for reducing the signs and symptoms of active arthritis, inhibiting the progression of structural damage and improving physical function in patients with psoriatic arthritis. HUMIRA can be used alone or in combination with methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs). HUMIRA is also approved for reducing signs and symptoms in patients with active AS. Earlier this year, HUMIRA was approved for reducing the signs and symptoms and inducing and maintaining clinical remission in adults with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy, and reducing the signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

In Europe, HUMIRA, in combination with methotrexate (MTX), is indicated for the treatment of moderate to severe, active RA in adult patients when the response to disease-modifying anti-rheumatic drugs (DMARDs) including MTX has been inadequate, and for the treatment of severe, active and progressive RA in adults not previously treated with MTX. HUMIRA can be given as monotherapy in case of intolerance to MTX or when continued treatment with MTX 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 MTX.

Additionally, HUMIRA is indicated for the treatment of active and progressive PsA in adults when the response to previous DMARD-therapy has been inadequate and for the treatment of severe, active AS in adults who have had an inadequate response to conventional therapy.

Abbott is focused on the discovery and development of innovative treatments for immunologic diseases. The Abbott Bioresearch Center, founded in 1989 in Worcester, Mass., United States, is a world-class discovery and basic research facility committed to finding new treatments for immune- mediated diseases.

In April 2007, Abbott announced the opening of Abbott Biotechnology Limited (ABL), its new state-of-the-art biologics manufacturing facility in Puerto Rico to support the long-term supply of HUMIRA. The new facility is the main manufacturing site for supplying HUMIRA to patients in the U.S.

More information about HUMIRA, including full prescribing information, is available on the Web site www.HUMIRA.com or in the United States by calling Abbott Medical Information at 1-800-633-9110.