Study Deems Long-Term Tocilizumab Safe for the Treatment of Rheumatoid Arthritis

Long-term monotherapy with tocilizumab (TCZ) showed continuous safety and efficacy at 5 years in patients with rheumatoid arthritis (RA) who participated in the AMBITION study.

The 24-week, randomized, controlled AMBITION study included patients with active RA who were either methotrexate (MTX)-naïve or MTX-free for 6 months prior to entering the study.

The participants were randomized to receive TCZ 8-mg/kg intravenously every 4 weeks or oral MTX weekly, with an initial dose of 7.5 mg and escalating to 20 mg. A subset of patients were enrolled in a placebo-controlled substudy and received placebo oral MTX and placebo IV infusions per week, at weeks 0, 4, and 8, followed by TCZ 8 mg/kg for 16 weeks.

At 24 weeks, patients were given the option to enroll in a long-term extension (LTE) study. The goal of the LTE study was to evaluate long-term safety and efficacy in patients treated with TCZ from their initial dose up to 264 weeks. Follow-up safety assessments continued for up to 276 weeks.

At week 24, patients in the LTE study who achieved ≥ 50% improvement from baseline in tender joint count (TJC) and swollen joint count (SJC) at weeks 20 and 24 could opt to continue their current blinded treatment in a transition phase until the last patient in the AMBITION study completed the study.

Efficacy was measured through the Disease Activity Score at 28 joints (DAS28), American College of Rheumatology (ACR) 20/50/70 responses, Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). Remission was defined as DAS28 < 2.6, SDAI ≤ 3.3, or CDAI ≤ 2.8.

In the AMBITION core study, a total of 286 patients received TCZ 8-mg/kg monotherapy, of whom 243 patients transitioned to the LTE study.

There were 134 patients who continued on monotherapy, and 109 who added a disease-modifying anti-rheumatic drug. By the end of the LTE period, 94 of 134 monotherapy patients remained in the study. Overall, 94 of 243 patients initially assigned to TCZ monotherapy who entered the LTE completed 5 years of TCZ monotherapy treatment.

Withdrawals due to safety reasons were reported for 19 patients, whereas 21 patients withdrew for non-safety reasons.

The time to maximum response for participants who continued on TCZ monotherapy throughout the core and LTE studies was approximately 130 weeks, and maintained through week 264.

The proportion of patients who achieved DAS28 clinical remission at 24 and 264 weeks was 40.2% and 65.2%, respectively. ACR20/50/70 responses at 24 and 264 weeks were 85.8%/56.7%/35.8% and 90.5%/77.9%/60%, respectively. The CDAI and SDAI remission rates were 61.5% and 20.3% at 24 weeks and 43% and 46.2% at 264 weeks.

“Therefore monotherapy showed durable and increasing efficacy over time,” the authors wrote.

The most common serious adverse events (SAEs) in monotherapy patients was infection, with the most frequent infection being pneumonia. There were no obvious associations between SAEs and duration of TCZ exposure observed. Furthermore, there were no new safety signals detected.

“AMBITION was the first trial to show the clinical efficacy and superiority of a biologic monotherapy compared with MTX monotherapy for typical MTX dosing regimens,” the authors wrote. “Results of the 5-year LTE study of AMBITION confirm the continued efficacy and safety of TCZ as monotherapy that has been demonstrated previously.”

Limitations to the study were a population enriched for patients who respond to treatment and those who do not experience tolerability issues. Efficacy results in the current study show nonresponder imputation, as well as observed data to help minimize bias associated with LTE.

“Long-term treatment of RA with TCZ monotherapy is an important option for patients who are unable to tolerate MTX or for who MTX is otherwise inappropriate,” the authors concluded.

The findings were published in The Journal of Rheumatology.