Centocor, a pharmaceutical company, issued two press releases on June 11, touting the positive results of its new TNF-inhibitor drug golimumab in three separate Phase III clinical trials. The results of the trials may help Centocor and Schering-Plough (working together to develop and market the drug) to move closer to receiving FDA approval for the drug for the treatment of Rheumatoid Arthritis, psoriatic arthritis and ankylosing spondylitis.
Centocor claims that all three studies show that patients taking golimumab experienced significant improvements in the signs and symptoms of RA, increased physical function and a decrease in disease activity. Golimumab is a TNF-inhibitor drug that is administered by subcutaneous injection once every four weeks in dosages of either 50 mg or 100mg. In each of the three studies, patients were also receiving methotrexate (MTX), sulfasalazine (SFZ) or hydrochloroquine(HCQ). The difference between the three studies was whether patients had previously taken MTX (the GO-FORWARD trial), had not previously taken MTX (GO-BEFORE trial) or if they had previously taken another TNF-inhibitor drug (GO-AFTER trial).
In the GO FORWARD study, GOlimumab FOR subjects With Active RA Despite MTX, patients whose disease was active despite ongoing treatment with MTX received either 50 mg or 100 mg doses of golimumab were studied in patients. It was a multi-center clinical trial that included 444 adult patients with active RA and more than four tender and swollen joints, despite MTX therapy. After 14 weeks of treatment, a little over 50 percent of patients receiving each dosage gained at least 20 percent improvement in signs and symptoms of RA (ACR 20), compared to 33 percent of patients receiving placebo and MTX. After this same time, about 75 percent of each group of golimumab patients were classified as DAS28 responders, meaning they had decreased disease activity, compared with 52 percent of patients receiving MTX alone. And about 34 percent of patients in the golimumab groups achieved remission compared with 13 percent of patients receiving placebo plus MTX.
After 24 weeks, about 70 percent of patients receiving golimumab experienced clinically relevant improvement in physical function, compared with 39 percent of patients receiving placebo plus MTX. The assessment of physical function was based on 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). Patients in the 100mg group had slightly higher percentages for improvement of all areas-signs, symptoms, disease activity and physical function than patients in the 50mg group. Centocor claims that patients experienced improvement early on in treatment (the first progress assessment was at week 4) and that they continued to improve over time through six months.
While anti-TNF therapies have been associated with serious and sometimes fatal risks (tuberculosis and other serious infections, cancers, heart failure, central nervous system disorders, reactivation of hepatitis B, and other serious events), Centocor reports that the drug was generally well-tolerated in RA patients. Through week 16, 61 percent receiving placebo plus MTX, 63 percent receiving golimumab 100 mg plus placebo, 69 percent receiving golimumab 50 mg plus MTX and 70 percent of patients receiving golimumab 100 mg plus MTX, reported at least one adverse event (AE). Two patients in the golimumab groups 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. One patient taking placebo plus MTX developed basal cell carcinoma. There were no reports of serious infection or tuberculosis.
In the GO-BEFORE study, GOlimumab Before Employing methotrexate as the First-line Option in the treatment of Rheumatoid arthritis of Early onset (GO-BEFORE), patients who had never taken MTX were treated with golimumab 50 mg or 100 mg in combination with MTX. The multi-center, double-blind, placebo controlled study included 637 adults with RA who had never taken MTX. Patients had active RA and more than four tender and swollen joints.
They also experienced improvement in signs and symptoms of arthritis as well as in disease activity. About 39 percent of patients in the combined golimumab plus MTX group achieved 50 percent improvement in signs and symptoms, compared with 29 percent of patients receiving placebo plus MTX. Additionally, 62 percent of patients in the combined golimumab plus MTX group achieved a 20 percent improvement in signs and symptoms, compared with 49 percent receiving placebo plus MTX. Also, 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 responders, and 38 percent achieved DAS 28 remission, compared with 61 percent and 28 percent of patients receiving placebo and MTX, respectively.
Through week 24, serious infections were reported in 1-4% of the four different study groups. Four patients reported malignancies, at least one from each group. 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 adverse events were reported in 3-6 percent of the patients.
Findings presented for GO-AFTER, GOlimumab After Former anti-TNF Therapy Evaluated in RA (GO-AFTER), showed that patients with moderately-to-severely active rheumatoid arthritis (RA) experienced significant improvements in signs and symptoms and physical function after receiving injections of golimumab of 50 mg or 100 mg once every four weeks. Investigators also reported that the patients who received golimumab showed sustained improvements in disease activity and physical function through six months. It was a multi-center, double-blind trial that included 461 patients with active RA for an average of about 8 years. All patients had previously received at least one anti-TNF-alpha agent (25 percent had previously been treated with two therapies and 9 percent with three) and discontinued them for lack of effectiveness, intolerance or other reasons. Patients were randomized to one of three treatment groups: SC placebo, golimumab 50 mg or golimumab 100 mg every four weeks. At baseline, 66 percent of patients were receiving MTX; 5 percent and 7 percent of patients were receiving SSZ and HCQ, respectively. Patients continued to receive stable doses of MTX, SSZ and/or HCQ if receiving them at baseline.
In the study, about 36% percent of patients receiving golimumab 50 mg and 100 mg, achieved at least 20 percent improvement in arthritis symptoms at week 14, compared with 18 percent of patients receiving placebo and maintained this improvement through six months. Of the 58 percent of patients whose prior anti-TNF alpha therapy had been discontinued due to lack of efficacy, 36 percent receiving golimumab 50 mg and 43 percent receiving golimumab 100 mg achieved ACR 20 as compared to 18 percent of patients treated with placebo.
Patients in both treatment groups receiving golimumab also experienced significant improvement in physical function and disease activity through six months. At 24 weeks, 52 percent of patients in the combined golimumab dosing group experienced a clinically relevant improvement in physical function, compared with 34 percent of patients receiving placebo. Additionally, at six months, more than half of patients in the combined golimumab group were classified as DAS28 responders, meaning they had decrease disease activity, compared with 23 percent and 25 percent of placebo-treated patients, respectively.
Similar to the other studies, Centocor reported that the drug was generally well tolerated in the GO-AFTER study. Through week 24, 72 percent, 66 percent and 78 percent of patients in the placebo, golimumab 50 mg and golimumab 100 mg groups, respectively, experienced at least one adverse event. Interestingly, they report that slightly more patients in the placebo group had adverse events than the golimumab groups. Serious infections were reported in 1-3% of patients depending on the group, and injection site reactions (ISR) through week 16 occurred in 3 percent, 4 percent and 11 percent of patients in the placebo, golimumab 50 mg and golimumab 100 mg groups, respectively. The most commonly reported ISR was erythema. No serious or severe ISRs were reported, and none of them caused people to discontinue participation.
Centocor and Schering-Plough seem to be optimistic about these study results. Hopefully, the data will stand up to increased scrutiny by the FDA, which is currently re-evaluating other TNF-inhibitors after reports of cancers in children. If golimumab is eventually approved, it will be another TNF-inhibitor treatment option for RA patients.
For more information see http://www.centocor.com
Published On: June 20, 2008