LONDON – The safety profile of tocilizumab in a prospective open-label study of rheumatoid arthritis patients with inadequate responses to biologics or disease-modifying antirheumatic drugs was comparable across the study’s monotherapy, dose-escalated combination therapy, and high-dose combination therapy treatment arms, Dr. Michael E. Weinblatt reported at the annual European Congress of Rheumatology.
This was the "first report of tocilizumab safety and efficacy in a real-world setting" in patients with disease progression, despite treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents. The study found the overall safety of the interleukin-6 monoclonal antibody was consistent with that observed in extension studies of the drug’s pivotal phase III program, said Dr. Weinblatt, who is a professor of medicine at Harvard Medical School and codirector of clinical rheumatology at Brigham and Women’s Hospital in Boston.
Dr. Michael E. Weinblatt
Of the 836 patients enrolled in Access to Therapy-Safety Trial of Adalimumab in Rheumatoid Arthritis (ACT-STAR), 183 patients who were on a biologic drug only prior to baseline were assigned to 8mg/kg tocilizumab (Actemra) monotherapy every 4 weeks. Another 363 and 360 patients, respectively, who were on DMARDs only or in combination with biologics prior to baseline were randomized to dose-escalating tocilizumab (starting at 4 mg/kg and increasing up to 8 mg/kg at physicians’ discretion) in combination with one or more DMARD or to 8 mg/kg tocilizumab in combination with one or more DMARD, Dr. Weinblatt reported in a late-breaking abstract session.
As per study protocol, all biologic drugs were discontinued prior to baseline, and patients randomized to the dose-escalating tocilizumab/DMARD condition who did not achieve at least 20% improvement in tender and swollen joint count had their tocilizumab dose increased to 8mg/kg, while others in that group could have their dose increased to 8mg/kg at the investigator’s discretion, Dr. Weinblatt explained. Patients on 8mg/kg tocilizumab plus DMARD could have their dose decreased at any time for safety reasons, he noted. The study’s primary outcome was the number of patients who experienced serious adverse events during the study period.
There was no statistical difference in the rates of serious adverse events across all three arms, Dr. Weinblatt reported. In the tocilizumab monotherapy group, eight patients (5.8%) had serious adverse events, leading to three treatment discontinuations and one dose modification. In the dose-escalation arm, 29 (8%) serious adverse events were reported, leading to seven dose modifications and 11 treatment discontinuations. In the high-dose tocilizumab group, 32 (8.4%) serious adverse events led to 11 dose modifications and four treatment discontinuations, he said. Two deaths not related to treatment occurred in the dose escalation group, he noted.
Serious infections were the most common serious adverse event, occurring in 3.6%, 3.9%, and 2.9% of patients in the dose-escalating, high-dose, and monotherapy groups, respectively, Dr. Weinblatt said. There were no reports of tuberculosis in any of the patients, he said. Three nonfatal gastrointestinal perforations occurred in the dose-escalating combination group, "all in patients with comorbidities," he stressed.
A total of 42 patients had abnormal liver function tests, including 26 with liver tests that were twice the upper limit of normal, 14 with values three times the upper limit of normal, and 2 with values exceeding five times the upper limit of normal. These findings are "similar to the values observed in the phase III extension studies, said Dr. Weinblatt. There were no significant between-group differences in the rates of uncommon lab abnormalities, he said.
With respect to treatment efficacy, DAS28 remission and mean change from baseline, and ACR20/50/70 responses were similar across all of the groups, Dr. Weinblatt said. "The results confirm that what we’ve seen in the research program translates to the real-world setting, with similar safety and efficacy numbers," he said in an interview. They also point to the possibility of the drug being used as a first-line agent as rheumatologists become more comfortable with it, particularly if it receives FDA approval for use as monotherapy in patients who have failed DMARDs, he said.
Dr. Weinblatt disclosed financial relationships with Abbott, Centocor Ortho Biotech, and Pfizer/Wyeth.