- Phase III monotherapy study shows ACTEMRA is first and only biologic to demonstrate statistical superiority over methotrexate after 24 weeks of
PARIS, June 13 /PRNewswire/ -- Patients who suffer the chronic and debilitating effects of rheumatoid arthritis (RA) -- despite treatment with current therapies -- achieved significant improvements in signs and symptoms when treated with Roche's ACTEMRA(R) (tocilizumab) alone or in combination with methotrexate compared with methotrexate alone, according to two international Phase III studies presented by researchers at the European Congress of Rheumatology (ECR) held by the European League Against Rheumatism (EULAR) in Paris.
Data from two new Phase III studies -- RADIATE and AMBITION trials -- will be highlighted as oral presentations at the congress, along with 21 additional abstracts involving ACTEMRA, a novel interleukin-6 (IL-6) receptor inhibitor being studied for the treatment of moderate to severe RA. Importantly, findings from the RADIATE study were also published online this week in the Annals of the Rheumatic Diseases.
In the RADIATE study, which evaluated difficult-to-treat patients who failed to respond to prior anti-TNF therapies, 50 percent of ACTEMRA-treated patients achieved a 20 percent (ACR20(1)) reduction in signs and symptoms. The AMBITION study showed that significantly more patients receiving ACTEMRA achieved a 20 percent improvement in their signs and symptoms [ACR20: 70%]. No previous biologic therapy has demonstrated statistically significant superiority compared to methotrexate in this important clinical parameter at week 24. In addition, nearly one-third of all ACTEMRA patients from both studies reached disease remission (as defined by DAS28 <2.6(2)).
"We are very encouraged by the results of the AMBITION study that shows for the first time that treatment with a single biologic agent is superior to methotrexate at six months of therapy," said Graeme Jones, M.D., lead investigator of the AMBITION trial and Associate Professor at the University of Tasmania in Hobart, Australia. "Overall, these compelling results further establish the efficacy and safety of ACTEMRA in treating the chronic signs and symptoms of RA that dramatically affect the lives of patients."
About AMBITION Study
The main AMBITION (Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy) study, a two-arm, randomized, double-blind, placebo-controlled study, was designed to evaluate the non-inferiority and subsequent superiority of ACTEMRA monotherapy in patients with RA compared with methotrexate alone at 24 weeks. Patients who had not received methotrexate for at least six months beforehand were randomized to receive either ACTEMRA (8 mg/kg) intravenously every four weeks plus placebo capsules weekly or placebo infusions every four weeks plus methotrexate weekly. The study evaluated 673 patients from 252 trial sites in 18 countries, including the United States.
In the AMBITION study, 70 percent, 44 percent and 28 percent of patients in the ACTEMRA (8 mg/kg) arm achieved ACR20, ACR50 and ACR70 compared, respectively, with 53 percent, 34 percent and 15 percent, respectively, of patients treated with methotrexate alone. Disease remission (DAS28 <2.6) was demonstrated in 34 percent of ACTEMRA patients compared with 12 percent of patients in the control group. A higher proportion of ACTEMRA (8 mg/kg) patients achieved a significant EULAR response(3) as early as the second week in the trial.
ACTEMRA was generally well tolerated; the most common adverse reactions reported more frequently in the ACTEMRA arm of the AMBITION trial were upper respiratory tract infections, headache and nasopharyngitis.
About RADIATE Study
The RADIATE (RheumAtoiD ArthritIs Study in Anti-TNF FailurEs) trial, a three-arm, randomized, double-blind, placebo-controlled study, was designed to evaluate the safety and efficacy of ACTEMRA plus methotrexate compared with placebo plus methotrexate in patients who failed to adequately respond to anti-TNF medications alone. Between 12-18 percent of the study population experienced three or more prior anti-TNF failures. Patients were randomized to receive either ACTEMRA intravenously (4 mg/kg or 8 mg/kg) plus methotrexate every four weeks or placebo infusions plus methotrexate weekly for 24 weeks. The study included 499 patients from 128 trial sites in 13 countries, including the United States.
In the study, 50 percent, 29 percent and 12 percent of RA patients treated with ACTEMRA (8 mg/kg) plus methotrexate achieved ACR20, ACR50 and ACR70, respectively, compared with 10 percent, 4 percent and 1 percent, respectively, of patients treated with placebo infusions plus methotrexate weekly.
Treatment with ACTEMRA and methotrexate showed significant clinical benefits even in the subgroup analysis of difficult-to-treat patients who received up to three anti-TNFs therapies that failed. Furthermore, disease remission (DAS28 <2.6) was demonstrated in 30 percent of ACTEMRA patients compared with 1.6 percent of patients in the control group.
The most common adverse reactions reported more frequently in the ACTEMRA arms of the RADIATE trial were nausea, headache, nasopharyngitis, diarrhea, and upper respiratory tract infections.
"These study results are very promising for RA patients who need a variety of treatment options, particularly when they have failed to achieve adequate pain and symptom relief with anti-TNF therapies," said Professor Paul Emery, lead study investigator of the RADIATE trial and Professor of Rheumatology, University of Leeds in the United Kingdom.
In both studies, patients treated with ACTEMRA alone or with methotrexate achieved greater improvements in quality-of-life measures, including fatigue, pain, and physical and mental functions, compared with methotrexate. Levels of C-reactive protein (CRP), a marker of inflammation and hemoglobin levels, showed significant and rapid improvement as early as two weeks in ACTEMRA (8 mg/kg) patients in the AMBITION trial, compared with patients treated with methotrexate alone.
"We are extremely pleased with these results which help us work toward establishing ACTEMRA as a new first-line biologic treatment, which blocks a different inflammatory target than current therapies. We are encouraged that we will soon be able to offer this new treatment option and meaningful benefit to those who need it the most -- the RA patients," said Lars Birgerson, M.D., Ph.D., Vice President, Global Head Medical Affairs, Roche.
About ACTEMRA (tocilizumab)
ACTEMRA is the first humanized interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody. Studies suggest that reducing the activity of IL-6, one of several key cytokines involved in the inflammatory process, may reduce inflammation of the joints and relieve certain systemic effects of RA. The extensive clinical development program conducted by Roche includes five clinical studies and has enrolled more than 4,000 patients in 41 countries, including the United States. Five Phase III studies are completed and have reported meeting their primary endpoints. The LITHE trial evaluating ACTEMRA in RA is an ongoing two-year study and is expected to report complete data evaluating the effects of ACTEMRA on the inhibition of structural joint damage in 2009. ACTEMRA is awaiting approval in the United States and Europe.
ACTEMRA is part of a co-development agreement with Chugai, a Japanese company. In June 2005, ACTEMRA was launched by Chugai in Japan as a therapy for Castleman's disease; in April 2008, additional indications for rheumatoid arthritis, juvenile idiopathic arthritis and systemic-onset juvenile idiopathic arthritis were also approved in Japan.
The serious adverse events reported in ACTEMRA clinical trials were serious infections and hypersensitivity reactions including anaphylaxis. The most common adverse events reported in clinical studies were upper respiratory tract infection, nasopharyngitis, headache and hypertension. Increases in liver function tests (ALT and AST) were seen in some patients; these increases were generally mild and reversible, with no hepatic injuries or any observed impact on liver function.
IL-6 is a common protein found in all joints in the body and is a natural substance that can raise inflammation. Everyone has IL-6 in their body, but people with RA may have too much. If approved, ACTEMRA will be the first and only medication to specifically target IL-6 in patients with RA.
About Rheumatoid Arthritis
Rheumatoid arthritis is a progressive, systemic autoimmune disease characterized by inflammation of the membrane lining in the joints. This inflammation causes a loss of joint shape and function, resulting in pain, stiffness and swelling, ultimately leading to irreversible joint destruction and disability. Characteristics of RA include redness, swelling, pain and movement limitation around joints of the hands, feet, elbows, knees and neck that leads to loss of function. In addition, the systemic symptoms of RA include fatigue, decreased hemoglobin, osteoporosis and may contribute to shortening life expectancy by affecting major organ systems. After 10 years, less than 50 percent of patients can continue to work or function normally on a daily basis. RA affects more than 21 million people worldwide with approximately 1.3 million adults affected in the United States.
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(1) ACR20, ACR50, ACR70 represent the percentage of reduction (20%, 50%,
70%) in certain RA symptoms and measures the number of tender and
swollen joints, pain, patient's and physician's global assessments and
certain laboratory markers.
(2) The Disease Activity Score (DAS)28 is a combined index that measures
disease activity in patients with RA. It combines information from 28
tender and swollen joints (range0-28), erythrocyte sedimentation rate,
and a general health assessment on a visual analog scale. The level of
disease activity is interpreted as low (DAS28 less than or equal to
3.2), moderate (3.2 (DAS28>5.1). DAS28<2.6 corresponds to being in remission according to the criteria of the American College of Rheumatology.
(3) The EULAR response criteria is based on the individual amount of change in DAS and the DAS value (low, moderate, high disease activity) reached to classify patients as good, moderate and non-responders.
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(DAS28>5.1). DAS28<2.6 corresponds to being in remission according to
the criteria of the American College of Rheumatology.
(3) The EULAR response criteria is based on the individual amount of
change in DAS and the DAS value (low, moderate, high disease activity)
reached to classify patients as good, moderate and non-responders.