Reports

Emerging Trends in the Treatment of Psoriasis
New Approaches to the Management of Male LUTS

IL-6 Receptor Inhibition in Rheumatoid Arthritis: New Insights from Clinical Trials

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - British Society for Rheumatology and British Health Professionals in Rheumatology Annual Conference

Glasgow, UK / April 28-May 1, 2009

Despite the availability of disease-modifying anti-rheumatic drugs (DMARDs) and new biologic agents for the treatment of rheumatoid arthritis (RA), there remains a significant unmet need in the RA population, according to Prof. John Isaacs, Newcastle University and the Freeman Hospital, Newcastle upon Tyne, UK. Only a minority of patients achieves clinical remission and 30% to 40% do not respond to existing biologic therapy. In patients who failed to respond to methotrexate (MTX), clinical trials of tumour necrosis factor (TNF) antagonists have shown that 60% of patients achieved an ACR20 response, 35% to 40% an ACR50 and 20% an ACR70. “This is true for all currently available biologics in MTX nonresponders,” Prof. Isaacs stated.

A number of new biologic agents are in late-phase development. Most recapitulate existing mechanisms of action and most require background MTX therapy for optimal efficacy. ACR response and remission rates are similar to existing agents. New agents are required that target novel mediators/cells. Prof. Isaacs defined the ideal profile of a new agent as one with a high rate of disease activity score (DAS) remission; efficacy on systemic manifestations of RA; and a lack of requirement for background MTX. No single target is likely to prove effective in all patients, he cautioned.

Interleukin-6 (IL-6), a pleiotropic pro-inflammatory cytokine produced by multiple cell types and involved in a wide range of physiological and pathological processes, has been identified as an alternative target for RA treatment. The humanized anti-IL-6 receptor antibody tocilizumab has shown efficacy in patients with DMARD-refractory RA in phase III clinical trials, both in combination with conventional DMARDs (the OPTION [Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders] and TOWARD [Tocilizumab in Combination with Traditional DMARD Therapy] trials); in combination with MTX in patients with an inadequate response to TNF antagonists (RADIATE [Rheumatoid Arthritis Study in Anti-TNF Failures]); and as monotherapy in patients who had not previously failed MTX or biologics (AMBITION [Tocilizumab versus Methotrexate Double-Blind Investigative Trial in Monotherapy]). Further insights from clinical trials were reported here during the scientific sessions.

AMBITION: Early vs. Late Disease

A sub-analysis of data from the AMBITION trial provides initial support for the early use of tocilizumab monotherapy in the management of RA patients who have not previously failed MTX or biologics, according to investigators led by Dr. Mark C. Genovese, Stanford University Medical Center, Palo Alto, California (Rheumatology [Oxford] 2009;48(Suppl 1):i86, Abstract 190). In AMBITION, patients were randomized to tocilizumab 8 mg/kg i.v. every four weeks or MTX monotherapy. Dr. Genovese and his colleagues stratified 570 patients into two subgroups according to disease duration at baseline: <2 years (241 patients) or <u>></u>2 years (329 patients). They found that at week 24, ACR response rates and DAS28 remission rates were significantly higher in patients receiving the IL-6 inhibitor compared with those receiving MTX in both subgroups. Rates of ACR responses tended to be higher and DAS28 remission rates were higher for tocilizumab and MTX in patients with disease duration <2 years compared with <u>></u>2 years (DAS28 <2.6: 41.7% vs. 28% and 18% vs. 7.3%, respectively). The incidence of adverse events (AEs) was similar in both subgroups for both treatments. More serum alanine aminotransferase elevations were seen in patients with RA disease duration <u>></u>2 years.

Safety of Long-term IL-6 Inhibition

The effects of prolonged IL-6 inhibition are unknown, but are being investigated in 2562 patients enrolled in two open-label extension studies of OPTION, TOWARD, RADIATE and AMBITION. Analysis of the pooled data after a median exposure to tocilizumab of 1.5 years showed that tocilizumab 8 mg/kg/MTX was well tolerated, with an incidence and type of AEs similar to those reported in the six-month controlled studies (Rheumatology [Oxford] 2009;48(Suppl 1):i86-i87, Abstract 192).

Rates of serious infection, malignancy and other serious AEs did not increase with continued treatment, as reported by Dr. Ronald F. van Vollenhoven, Karolinska University Hospital, Stockholm, Sweden, and colleagues. The most common AEs were infections (36%), gastrointestinal disorders (22%), skin and subcutaneous disorders (14%) and elevations in lipids and liver enzymes (15%). The most common AEs leading to withdrawal (6.2% of patients) were neoplasms (1.1%), liver enzyme elevations (1%) and infections (0.9%). Elevations in lipids seen at six months stabilized after that time.

Inhibition of Structural Joint Damage

IL-6 inhibition significantly inhibits the progression of structural joint damage and significantly improves physical function in patients with RA, according to one-year data from the ongoing LITHE trial (Rheumatology [Oxford] 2009;48(Suppl 1):i93, Abstract 212). The LITHE trial is investigating the efficacy of tocilizumab 4 or 8 mg/kg/MTX vs. placebo/MTX in the prevention of joint damage in 1195 patients with moderate-to-severe active RA who have had an inadequate response to MTX.

Researchers led by Dr. Joel M. Kremer, Albany Medical College and The Center for Rheumatology, New York, reported that the mean change in combined Genant-modified Sharp radiographic score was lower in patients in the combination arm vs. MTX/placebo (0.34 [4 mg] and 0.29 [8 mg] vs. 1.13, respectively; both P<0.001). In addition, 80.5% and 84.5% of patients treated with tocilizumab 4 mg/kg or 8 mg/kg, respectively, showed no radiographic progression of either joint erosion or joint space narrowing compared with 67.2% of patients on placebo. Analysis of the AUC for the change from baseline in the Health Assessment Questionnaire Disability Index showed significantly greater decreases with tocilizumab 4 mg/kg and 8 mg/kg vs. MTX (30.2% and 47.2% vs. 7.9%; both P<0.0001), indicating improved physical function over 52 weeks.

RADIATE: IL-6 Inhibition Following Inadequate Responses to TNF Antagonists

An exploratory post-hoc analysis of data from the RADIATE trial, presented by Prof. Paul Emery, Institute of Molecular Medicine, University of Leeds, UK, showed that clinical outcomes improved with IL-6 inhibition irrespective of the number of TNF antagonists previously prescribed (Rheumatology [Oxford] 2009;48(Suppl 1):i19, Abstract OP51). RADIATE involved 499 patients who were randomized to treatment with tocilizumab 4 or 8 mg/kg or placebo administered intravenously (i.v.) every four weeks with stable MTX for 24 weeks. “What was unique to the study was that with the 8 mg/kg dose of tocilizumab, there was no fall-off in ACR20 response irrespective of whether patients had failed one, two or three TNF antagonists,” Prof. Emery noted. In patients treated with 8 mg/kg who had one, two or three inadequate responses to TNF antagonists, DAS28 remission rates were 30.9%, 31.4% and 25%, respectively, rates not previously seen in patients who previously failed TNF antagonists, Prof. Emery stressed. Both doses were generally well tolerated; no pattern in the incidence of adverse effects was observed according to treatment group or number of prior TNF antagonists failed.

IL-6 Inhibition and Other Biologic Agents

Since no comparative studies have been carried out to assess the efficacy of different biologic agents, researchers have carried out a meta-analysis using data from clinical trials with abatacept (two), rituximab (two), TNF antagonists (11) and tocilizumab (three) (Rheumatology [Oxford] 2009;48(Suppl 1): i84, Abstract 185). The 18 studies had follow-up periods of 24 or 30 weeks and involved a total of 10,419 patients. Compared with placebo, tocilizumab had a higher probability of response than other biologic agents in all response categories.

Efficacy was similar for all agents in terms of ACR20 and ACR50 responses, but tocilizumab had a significantly increased ACR70 relative response compared with TNF inhibitors and abatacept. Based on an adjusted placebo ACR70 response from all trials (4.2%), tocilizumab was estimated to have a 29% response rate at ACR70 compared with 16%, 15% and 18% response rates for TNF antagonists, abatacept and rituximab, respectively.

Note: At press time, tocilizumab is not available in Canada.

We Appreciate Your Feedback

Please take 30 seconds to help us better understand your educational needs.