An international trial found that the new drug tociluzumab, when given in combination with methotrexate, was fast, effective and reasonably tolerated compared to placebo in treating patients with rheumatoid arthritis that had not responded to TNF therapy.

The study was the work of Professor Paul Emery of the University of Leeds in the UK and colleagues from other research centres in Canada, Germany, France, Sweden, Mexico and the US and was presented on Monday 27 October in San Francisco, California at the Annual Scientific Meeting of the American College of Rheumatology and Association of Rheumatology Health Professionals.

Rheumatoid arthritis is a complex disease where the immune system attacks healthy joints to cause inflammation and pain, with some patients responding well to some therapies while others do not. Tumor necrosis factor (TNF) antagonist therapy is one such treatment where some patients either do not respond well enough or the treatment becomes less effective over time.

Tociluzumab is a new monoclonal antibody that stops interleukin-6 (IL-6) signalling and has been suggested as a potential alternative treatment for patients who do not respond to TNF. Tociluzumab prevents the release of a pro-inflammatory protein secreted by immune system cells and thus reduces the inflammation and pain in the joints.

Tociluzumab will be marketed by Roche under the brand name RoActemra which is currently awaiting approval in Europe and the US.

The Research on Actemra Determining effIcacy after Anti-TNF failurEs (RADIATE) trial investigated the safety and effectiveness of tociluzumab in combination with methotrexate in rheumatoid arthritis patients who did not respond well to TNF.

For the multicenter, randomized, double-blind study, Emery and colleagues investigated 499 patients who had had moderate to severe rheumatoid arthritis for more than 6 months.

All the patients had experienced an inadequate response to TNF and had been on a stable dose of methotrexate for the 12 weeks leading up to the start of the trial period (baseline).

The patients were randomized to a placebo (control) group (10 – 25 mg a week of methotrexate and iv placebo) and two treatment groups (10 – 25 mg a week of methotrexate and 4 or 8 mg/kg iv of tociluzumab). They received their medication every 4 weeks for 24 weeks.

The results showed that:

  • All the outcomes in the 8 mg/kg and most in the 4 mg/kg tociluzumab groups were significantly better than in the placebo group.

  • 25, 34 and 60 per cent of patients respectively withdrew or needed rescue therapy.

  • Statistical tests showed patients on the 8 mg/kg tociluzumab were 9 times more likely to achieve an ACR20 response at week 24 compared to controls.

  • An ACR20 response at week 24 for patients on the 4 mg/kg tociluzumab was 4 times more likely than for control patients.

  • By week 4 there was a clear ACR20 difference between the 8 mg/kg tociluzumab patients and controls.

  • By week 8 there was a clear ACR50 and ACR70 difference in these same groups.

  • In both tociluzumab treatment groups, DAS28 remission was first reached by week 2 (1.3 per cent of the 4 mg/kg group and 1.9 per cent of the 8 mg/kg group).

  • DAS28 remission was first achieved in the control group by week 12 (0.7 per cent of patients).

  • Remission as measured by DAS28 continued to improve to 30 per cent at week 24 in the 8 mg/kg tociluzumab group.

  • Adverse events occurred in 84.0 per cent of the 8 mg/kg tociluzumab group, 87.1 per cent of the 4 mg/kg tociluzumab group, and 80.6 per cent of the placebo group.

  • Common adverse events included: diarrhea, upper abdominal pain, rash and dizziness.

  • Serious adverse events occurred in 6.3 per cent of the 8 mg/kg tociluzumab group, 7.4 per cent of the 4 mg/kg tociluzumab group, and 11.3 per cent of the placebo group.

  • Serious infections occurred in 4.6, 1.8 and 3.1 per cent of the groups respectively.

ACR20 is a measure that looks for a 20 per cent improvement in tenderness and swelling across a range of endpoints. ACR50 and 70 look for 50 and 70 per cent improvements.

DAS28 is a disease activity measure (DAS) that takes into account the amount of swelling and tenderness in 28 different joints plus a marker of inflammation present in the bloodstream.

Emery and colleagues concluded that:

“TCZ [tociluzumab] +MTX [methotrexate] therapy was associated with rapid and significant clinical improvements in this anti-TNF IR [inadequate response] population. 30 per cent of patients achieved remission with the 8 mg/kg dose. Treatment was reasonably safe and well tolerated.”

“Tociluzumab (TCZ) Rapidly and Significantly Improves Outcomes in Patients with Rheumatoid Arthritis (RA) Who Have Inadequate Response (IR) to TNF Antagonists.”
P. Emery, E. Keystone, HP Tony, A. Cantagrel, R. van Vollenhoven, A. Sanchez, E. Alecock, J. Lee, J. Kremer.
Presented Monday 27 October 2008 at ACR/ARHP Annual Scientific Meeting, San Francisco, California.

Click here for American College of Rheumatology.

Sources: ACR/ARHP.

Written by: Catharine Paddock, PhD.