Healthcare Industry News: Methotrexate
News Release - June 11, 2008
Data From Two Phase 3 Studies Show Anti-TNF Golimumab Significantly Improved Signs and Symptoms of Rheumatoid ArthritisPatients Receiving Every Four-Week Subcutaneous Golimumab Also Experienced Improvements in Physical Function and Disease Activity
PARIS, June 11 (HSMN NewsFeed) -- Findings from two new Phase 3 studies showed that patients receiving every four-week subcutaneous injections of golimumab (CNTO 148) 50 mg and 100 mg and weekly Methotrexate (MTX) experienced significant improvements in the signs and symptoms of rheumatoid arthritis (RA) as well as in physical function and disease activity, with some patients achieving remission as measured by Disease Activity Score (DAS28). Findings from two multicenter, randomized, double-blind, placebo-controlled Phase 3 studies showed the efficacy of golimumab in two important populations - MTX-naive patients and patients with active RA despite ongoing treatment with MTX. These data were presented at the European League Against Rheumatism (EULAR) Annual Congress of Rheumatology. Golimumab is currently in the most comprehensive initial Phase 3 development program to date for an anti-tumor necrosis factor (TNF)-alpha biologic therapy with ongoing studies for the treatment of RA, psoriatic arthritis and ankylosing spondylitis.
In the study, GOlimumab FOR subjects With Active RA Despite MTX (GO-FORWARD), both the 50 mg and 100 mg doses of golimumab were studied in patients whose disease was active despite ongoing treatment with MTX. At week 14, 55 percent of patients receiving golimumab 50 mg plus MTX and 56 percent receiving golimumab 100 mg plus MTX achieved at least 20 percent improvement in signs and symptoms of RA (ACR 20), compared to 33 percent of patients receiving placebo and MTX (p<0.01 and p<0.001, respectively). Improvements were seen as early as first clinical assessment, which was four weeks after the first golimumab injection, and generally continued to improve over time.
"The data in this study demonstrate that golimumab is beneficial in improving numerous disease parameters, including inducing remission, in patients whose disease was active despite ongoing treatment with Methotrexate," said Edward Keystone, M.D., FRCPC, director of the Rebecca MacDonald Centre for Arthritis & Autoimmune Disease at Mount Sinai Hospital in Toronto, and lead study investigator. "Since some patients do not respond adequately to Methotrexate alone, this combination therapy could prove to be a highly valuable treatment option based on these results."
Patients receiving golimumab also experienced improvement in physical function as assessed by the Health Assessment Questionnaire (HAQ). At 24 weeks, 68 percent of patients in the golimumab 50 mg dosing group and 72 percent of patients receiving golimumab 100 mg experienced clinically relevant improvement in physical function (improvement in HAQ score of at least 0.25 from baseline), compared with 39 percent of patients receiving placebo plus MTX (p<0.0001). HAQ assess the degree of difficulty a patient has in accomplishing tasks in eight functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and other activities of daily living).
At week 14, 74 percent and 76 percent of patients in the golimumab 50 mg and 100 mg plus MTX groups, respectively, were classified as DAS28 (using C-reactive protein [CRP]) responders, compared with 52 percent of patients receiving MTX alone (p<0.001). Importantly, 35 percent and 32 percent of patients in the respective golimumab groups achieved remission based on DAS28 (CRP), compared with 13 percent of patients receiving placebo plus MTX (p<0.001). These improvements were sustained through six months.
In another Phase 3 study, GOlimumab Before Employing Methotrexate as the First-line Option in the treatment of Rheumatoid arthritis of Early onset (GO-BEFORE), MTX-naive patients treated with golimumab 50 mg or 100 mg in combination with MTX experienced improvement in signs and symptoms of arthritis as well as in disease activity. The study's primary endpoint was based on an intent-to-treat (ITT) analysis, which included all patients randomized in the study. However, three patients did not receive study drug but were included in the analysis as nonresponders. In the primary analysis of the combined group of patients receiving either golimumab 50 mg or 100 mg in combination with MTX, 38 percent (40 percent receiving 50 mg and 37 percent receiving 100 mg) achieved at least 50 percent improvement in signs and symptoms of RA (ACR 50) through week 24, compared with 29 percent of patients receiving placebo plus MTX (p=0.053 for the combined group, p=0.042 for 50 mg and p=0.177 for 100 mg). When the three patients who did not receive golimumab were excluded in a modified intent-to-treat (mITT) analysis, the results showed that 39 percent of patients in the combined golimumab plus MTX group (41 percent receiving 50 mg and 37 percent receiving 100 mg) achieved ACR 50, compared with 29 percent of patients receiving placebo plus MTX (p=0.049 for the combined group, p=0.038 for 50 mg and p=0.177 for 100 mg). Additionally, 62 percent of patients in the combined golimumab plus MTX group (62 percent for each dose group) achieved ACR 20, compared with 49 percent receiving placebo plus MTX (p=0.011 for the combined group and p=0.028 for each dose group).
"These data show that treatment with golimumab induces an important depth of response, improving multiple aspects of rheumatoid arthritis and leading to significant decreases in disease activity," said Roy Fleischmann, M.D., Clinical Professor, Department of Internal Medicine at the University of Texas Southwestern Medical Center; Chief, Division of Rheumatology at St. Paul University Hospital in Dallas, Texas and lead study investigator. "Golimumab, which is an anti-TNF therapy, is a promising treatment option for multiple patient populations with this chronic and potentially debilitating inflammatory disease."
Also at week 24, patients receiving golimumab plus MTX experienced improvements in disease activity as measured by DAS28. Seventy-six percent of patients in the combined golimumab group were classified as DAS28 (CRP) responders, and 38 percent achieved DAS 28 remission, compared with 61 percent and 28 percent of patients receiving placebo and MTX, respectively (p<0.001 for responders and p=0.031 for remission).
"We are encouraged by the findings of both of these Phase 3 studies," said Robert J. Spiegel, M.D., chief medical officer, Schering-Plough Research Institute. "Golimumab holds great promise as an anti-TNF therapy for patients who may benefit from monthly subcutaneous injections for RA and related rheumatic diseases."
In March 2008, Centocor Inc. and Schering-Plough Corporation (NYSE: SGP ) announced that a Marketing Authorization Application (MAA) had been submitted to the European Medicines Agency requesting the approval of golimumab as a monthly subcutaneous treatment for adults with RA, psoriatic arthritis and ankylosing spondylitis. The initial submission and Phase 3 development programs are unprecedented among anti-TNF-alpha therapies, as they mark the first time that an MAA has been proposed for review inclusive of three unique disease states. Golimumab, Centocor's and Schering-Plough's next-generation human anti-TNF-alpha monoclonal antibody, is being studied as an every four-week subcutaneous injection and an intravenous (IV) infusion therapy.
About the GO-FORWARD Trial
GO-FORWARD, a Phase 3, multi-center clinical trial included 444 patients with active RA. Adult patients with more than four tender and swollen joints, despite MTX therapy, were randomly assigned to receive golimumab (50 or 100 mg) plus MTX, golimumab 100 mg plus placebo or placebo plus MTX at weeks 0, 4, 8, 12, 16 and 20. Data were assessed at weeks 14 and 24. The co-primary endpoints were percentage of patients achieving ACR 20 response at week 14 and improvement from baseline in HAQ at week 24.
Golimumab was generally well-tolerated in RA patients. Through week 16, 61 percent, 63 percent, 69 percent and 70 percent of patients receiving placebo plus MTX, golimumab 100 mg plus placebo, golimumab 50 mg plus MTX and golimumab 100 mg plus MTX, respectively, reported at least one adverse event (AE). Three patients participating in the study developed malignancies: one patient taking golimumab 100 mg plus MTX developed breast cancer, one patient taking golimumab 100 mg plus placebo developed Bowen's disease and one patient taking placebo plus MTX developed basal cell carcinoma. There were no reports of opportunistic infection or tuberculosis.
About the GO-BEFORE Trial
GO-BEFORE, a Phase 3, multi-center, double-blind, placebo controlled study included 637 MTX-naive adults with RA. Patients with active RA who had more than four tender and swollen joints were included in the multicenter study. Adult patients were randomly assigned into four groups to receive placebo every four weeks plus MTX 20 mg per week (Group 1), golimumab 100 mg every four weeks plus placebo every week (Group 2), golimumab 50 mg every four weeks plus MTX 20 mg per week (Group 3), or golimumab 100 mg every four weeks plus MTX 20 mg per week (Group 4).
AEs were generally similar across the four patient groups. Through week 24, serious infections were reported in 2 percent, 1 percent, 1 percent and 4 percent of Groups 1-4, respectively. Four patients reported malignancies during the study: two patients from Group 1 and one patient each from Groups 3 and 4. There were also two deaths during the study -- one patient in Group 3 committed suicide, and one patient from Group 4 died from cardiac arrest following a surgical procedure. Overall, serious AEs were reported in 7 percent, 3 percent, 6 percent and 6 percent of patients in Groups 1-4, respectively.
Anti-TNF therapies have been associated with serious and sometimes fatal risks, including the risk of tuberculosis and other serious infections, malignancies, heart failure, central nervous system disorders, reactivation of hepatitis B, and other serious events.
About Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic and debilitating disease that affects approximately 1.3 million people in the United States and more than three million people in Europe. Signs and symptoms of RA include pain, stiffness and motion restriction in multiple joints. Because RA is a progressive disease, it can cause permanent joint deformity and severe disability if not diagnosed early or if initial treatment is delayed. RA can occur at any age, but is most common in adults 30-50 years old and is two-to-three times more prevalent in women than in men. The cause of RA is unknown, although genetic factors may contribute to the disease.
Golimumab, Centocor Inc.'s and Schering-Plough Corporation's next-generation human anti-TNF-alpha monoclonal antibody, is currently in the most comprehensive Phase 3 development program to date for an anti-TNF-alpha biologic therapy. With ongoing studies for the treatment of RA, psoriatic arthritis and ankylosing spondylitis, golimumab is being studied as an every four-week subcutaneous injection and an IV infusion therapy. Golimumab targets and neutralizes both the soluble and membrane-bound forms of TNF-alpha.
Centocor discovered golimumab and has exclusive marketing rights to the product in the United States. Pending regulatory approval, Schering-Plough will assume exclusive marketing rights outside the United States except in Japan, Indonesia and Taiwan where golimumab will be co-marketed by Mitsubishi Tanabe Pharma Corporation and Janssen Pharmaceutical Kabushiki Kaisha; Hong Kong, where golimumab will be exclusively marketed by Janssen-Cilag; and China where golimumab will be exclusively marketed by Xian-Janssen.
Centocor is harnessing the power of world-leading research and biomanufacturing to deliver innovative biomedicines that transform patients' lives. Centocor has already brought innovation to the treatment of Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, ulcerative colitis, pediatric Crohn's disease and psoriasis.
The world leader in monoclonal antibody production and technology, Centocor has brought critical biologic therapies to patients suffering from debilitating immune disorders. Centocor is a wholly-owned subsidiary of Johnson & Johnson.
CENTOCOR DISCLOSURE NOTICE: This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from Centocor's expectations and projections. Risks and uncertainties include general industry conditions and competition; economic conditions, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 30, 2007. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Centocor does not undertake to update any forward-looking statements as a result of new information or future events or developments.
Schering-Plough is an innovation-driven, science-centered global health care company. Through its own biopharmaceutical research and collaborations with partners, Schering-Plough creates therapies that help save and improve lives around the world. The company applies its research-and-development platform to human prescription and consumer products as well as to animal health products. Schering-Plough's vision is to "Earn Trust, Every Day" with the doctors, patients, customers and other stakeholders served by its colleagues around the world. The company is based in Kenilworth, N.J., and its Web site is www.schering-plough.com.
SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this press release includes certain "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the potential market for Golimumab. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough's forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Part I, Item IA. "Risk Factors" in Schering-Plough's 2008 Q1 10-Q.
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