ACTEMRA (R) (tocilizumab) Significantly Reduced Signs And Symptoms Of Rheumatoid Arthritis In Patients Who Failed Prior Treatments

Main Category: Arthritis / Rheumatology
Also Included In: Clinical Trials / Drug Trials;  Conferences;  Pharma Industry / Biotech Industry
Article Date: 28 Oct 2008 - 0:00 PDT

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Data from two Phase III studies showed that patients who suffer from the debilitating and painful effects of rheumatoid arthritis (RA) achieved significant improvements in signs and symptoms when treated with ACTEMRA(R) (tocilizumab) alone or in combination with methotrexate compared with methotrexate alone. The final results of both studies will be presented as oral presentations, along with 13 other abstracts which evaluate ACTEMRA in patients with moderately to severely active RA, at the American College of Rheumatology (ACR) Annual Scientific Meeting in San Francisco, October 24-29.

Results of the RADIATE study, which evaluated difficult-to-treat patients who failed to respond to prior anti-tumor necrosis factor (TNF)-alpha therapies, demonstrated that half of patients treated with ACTEMRA (8 mg/kg) in combination with methotrexate achieved a 20 percent reduction (ACR20)(1) in RA signs and symptoms, compared with 10 percent of patients treated with methotrexate alone.

"Despite treatment with existing therapies, many patients with RA continue to experience symptoms of joint pain and stiffness," said Mark Genovese, M.D., Professor of Medicine at Stanford University School of Medicine. "The compelling results of these studies further support the efficacy and safety of ACTEMRA as a potential new treatment option for managing the chronic signs and symptoms of this debilitating disease."

The AMBITION study, which examined the effects of ACTEMRA (8 mg/kg) as monotherapy, showed that 70 percent of patients receiving ACTEMRA achieved a 20 percent improvement in their signs and symptoms (ACR20), compared with 53 percent of patients receiving methotrexate alone. The study not only successfully met its primary endpoint of non-inferiority in patients with moderate to severe RA, but also demonstrated superiority over the standard effective dose regimen of methotrexate alone.

In both studies, nearly one-third of all ACTEMRA (8 mg/kg) patients achieved disease remission (as defined by DAS28 <2.6(2)) and ACTEMRA was generally well-tolerated compared with existing therapies.

About the RADIATE Study

RADIATE (RheumAtoiD ArthritIs Study in Anti-TNF FailurEs), 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-alpha medications alone.? Between 13-17 percent of the study population experienced three or more prior anti-TNF-alpha 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 nearly 500 patients from 128 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, and 30 percent, 17 percent and 5 percent of patients in the ACTEMRA 4 mg/kg arm achieved these ACR scores, respectively. In contrast, 10 percent, 4 percent and 1 percent of patients in the control group achieved ACR20, ACR50 and ACR70, respectively. Furthermore, disease remission (DAS28 <2.6) was demonstrated in 30 percent and 8 percent of patients treated with ACTEMRA 8 mg/kg and 4 mg/kg, respectively, compared with 1.6 percent of patients in the control group.

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-TNF-alpha therapies that failed.

The most common adverse reactions reported most frequently in the ACTEMRA arms of the RADIATE study were diarrhea, upper abdominal pain, rash and dizziness.

About the AMBITION Study

AMBITION (Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy), 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 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, respectively, compared 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 study. Levels of C-reactive protein (CRP), a marker of inflammation, and hemoglobin levels showed rapid normalization in as early as two weeks in ACTEMRA (8 mg/kg) patients in the AMBITION study, compared with patients treated with methotrexate alone.

ACTEMRA was generally well tolerated and the adverse event rates were similar in the group treated with ACTEMRA compared with patients treated with methotrexate alone (80 percent and 78 percent, respectively).

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.

About ACTEMRA(R) (tocilizumab)

ACTEMRA is the first humanized interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody studied for the treatment of RA. Studies demonstrate that reducing the activity of IL-6, one of several key cytokines involved in the inflammatory process, relieves both inflammation of the joints and certain systemic effects of RA. The extensive clinical development program conducted by Roche includes five Phase III clinical studies and has enrolled more than 4,000 patients in 41 countries, including the United States. Four Phase III studies are completed and have reported meeting their primary endpoints. A fifth Phase III study, the LITHE trial evaluating ACTEMRA in RA is an ongoing two-year study, which is expected to report complete data evaluating the effects of ACTEMRA on the inhibition of structural joint damage in 2009. ACTEMRA is currently under review in the United States and Europe.

ACTEMRA is part of a co-development agreement between Roche and Chugai Pharmaceutical Co. 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 reactions reported in ACTEMRA clinical studies include serious infections, gastrointestinal perforations and hypersensitivity reactions including anaphylaxis. The most common adverse reactions reported in clinical studies were upper respiratory tract infection, nasopharyngitis, headache, hypertension and increased ALT. Increases in liver enzymes (ALT and AST) were seen in patients; these increases were generally mild and reversible, with no evidence of hepatic injuries. Laboratory changes, including increases in lipids (total cholesterol, LDL, HDL, triglycerides) and decreases in neutrophils and platelets, were seen in patients without association with clinical outcomes. Treatments that suppress the immune system, such as ACTEMRA, may cause an increase in the risk of malignancies.

About IL-6

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. When 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.

About Roche

Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. pharmaceuticals headquarters of the Roche Group, one of the world's leading research-oriented healthcare groups with core businesses in pharmaceuticals and diagnostics. For more than 100 years in the U.S., Roche has been committed to developing innovative products and services that address prevention, diagnosis and treatment of diseases, thus enhancing people's health and quality of life. An employer of choice, in 2007 Roche was named Top Company of the Year by Med Ad News, one of the Top 20 Employers (Science) and ranked the No. 1 Company to Sell For (Selling Power). In previous years, Roche has been named as a Top Company for Older Workers (AARP) and one of the Best Companies to Work For in America (Fortune). For additional information about the U.S. pharmaceuticals business, visit our websites: http://www.rocheusa.com or http://www.roche.us.

All trademarks used or mentioned in this release are protected by law.

References

(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 (range 0-28), 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 (3.25.1).

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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