The IL-6 Receptor Antagonist Tocilizumab Shows Promise for the Treatment of RA

The IL-6 Receptor Antagonist Tocilizumab Shows Promise for the Treatment of RA

Il-6 is a highly inflammatory cytokine that is produced in abundance in RA. It has many pathogenic effects involved in the amplification of the inflammatory response and in direct destruction of bone and cartilage. Tocilizumab, a humanized monoclonal antibody directed against the human IL-6 receptor (also known as MRA), has been shown to be effective against placebo as monotherapy in RA in short-term, dose-finding studies (see data) and in juvenile idiopathic arthritis (JIA) (see data). Here, Maini et al (Arthritis Rheum 2006; 54: 2817) report the results of the CHARISMA (Chugai Humanized Anti-Human Recombinant Interleukin-Six Monoclonal Antibody) Study, the largest trail to date of tocilizumab in RA patients with an inadequate response to methotrexate (MTX).

Methods: Subjects were recruited from 57 centers in Europe. Subjects were required to have active RA (> 6 swollen and > 6 tender joints and elevated inflammatory markers) and an inadequate response to at least 6 months of methotrexate therapy at 10 to 25 mg per week. Patients receiving other current DMARDs or TNF inhibitors within the prior 3 months were excluded. Safety exclusions included leukopenia, thrombocytopenia, and evidence of hepatic or renal dysfunction.

Eligible subjects were randomized to one of seven groups:

  1. Tocilizumab 2mg/kg IV every 4 weeks + background MTX
  2. Tocilizumab 4mg/kg IV every 4 weeks + background MTX
  3. Tocilizumab 8mg/kg IV every 4 weeks + background MTX
  4. Tocilizumab 2mg/kg IV every 4 weeks + placebo MTX
  5. Tocilizumab 4mg/kg IV every 4 weeks + placebo MTX
  6. Tocilizumab 8mg/kg IV every 4 weeks + placebo MTX
  7. Placebo tocilizumab infusion every 4 weeks + background MTX

Subjects received four infusions, with efficacy endpoints determined at 16 weeks. ACR20 response at 16 weeks was the primary efficacy endpoint, with ACR50 and 70 responses, DAS28, and EULAR response criteria as secondary endpoints. Subjects withdrawing prior to 16 weeks for lack of efficacy were classified as non-responders. Safety assessments were performed at week 20.

Results: 359 subjects were randomized, with 49 to 54 subjects in each of the seven groups. Baseline characteristics were typical for RA therapeutic trials, with 79% of the subjects being female with an average age of approximately 50 years. The range of mean RA disease duration was 7.82 to 11.24 years between groups. Baseline DAS28 scores were between 6.34 and 6.75 between groups. Rheumatoid factor seropositivity was observed in 83% of subjects. Background MTX dosing tended to be in the 10 to 17.5 mg per week range, with a minority of patients receiving higher weekly doses prior to enrollment. Baseline characteristics were statistically balanced between treatment allocations.

Efficacy Endpoints

Proportion of subjects achieving ACR20, 50, or 70 responses according to treatment allocation

Response at 16 weeks Control Monotherapy Combination Therapy
MTX MRA
2mg/kg
MRA
4mg/kg
MRA
8mg/kg
MRA
2mg/kg
MRA
4mg/kg
MRA
8mg/kg
ACR20 41 31 61* 63* 64* 63* 74*
ACR50< 29 6 28 41 32 37 53*
ACR70 16 2 6 16 14 12 37*

*indicates response significantly different from control response (p < 0.05)

DAS28 responses were comparable to ACR responses. DAS remission was achieved in 8% of the patients in the MTX control group, 17% of the tocilizumab 8 mg/kg monotherapy treated subjects, and 34% of the tocilizumab 8 mg/kg combination therapy treated subjects.

Safety Endpoints
In general, non-serious adverse events did not differ between active treatment groups and control. However, serious treatment-related serious adverse events did appear to be increased in the subjects receiving tocilizumab compared to control. Thirty five of the 359 enrolled subjects (9.7%) experienced a serious treatment-related adverse event, 33 in the 310 tocilizumab treated subjects (10.6%) compared to 2 in the 49 control subjects (4.1%). Seven serious infections occurred, all in tocilizumab treated subjects (4 in 3 subjects receiving 2 mg/kg monotherapy and 3 in 3 subjects receiving 8 mg/kg combination therapy) and included limb abcess/osteomylelitis, pleural infection, lower respiratory tract infection, infective arthritis, 2 cases of sepsis, one of which was identified as S. aureus. The last 3 infections occurred in subjects receiving tocilizumab 8 mg/kg combination therapy. No cases of tuberculosis or other opportunistic infection wee noted.

Increases in transaminases, bilirubin, and lipids (total cholesterol, HDL cholesterol, and triglycerides) were observed after infusions of tocilizumab, some markedly elevated. However, none of these findings were found to be clinically significant during the course 20 week safety monitoring phase of the trial. A dose related decrease in neutrophils was also noted, some of which fulfilled criteria for neutropenia. However, subjects with decreased neutrophils were not found to have higher infection rates than those without decreased neutrophils.

Conclusion: Tocilizumab, particularly at a dose of 8 mg/kg in combination with background methotrexate, is effective at improving the signs and symptoms of active RA in patients with inadequate response to methotrexate monotherapy. Certain drug-related safety issues warrant further investigation.

Editorial Comment: Because of its novel cytokine target, tocilizumab is a welcome addition to the repertoire of cytokine antagonists. Indeed, it is likely that a subset of RA patients, those whose disease may be more IL-6-driven rather than driven by other cytokines, will have a favorable response to tocilizumab. In addition, the drug holds promise for applications in other IL-6 driven inflammatory disorders, such as JIA and Stills disease.

Within the context of this study, the effect of background methotrexate is evident, with more than half to as much as two-thirds of the effect of the active study drug on ACR20 response accounted for by background methotrexate. Head-to-head studies of methotrexate monotherapy vs. tocilizumab monotherapy in DMARD nave patients are needed to explore this relationship more completely.

The variety of safety issues encountered require further investigation; in particular whether serious adverse events increase with prolonged duration of therapy. The dose-related increase in serious potentially life-threatening bacterial infections is especially concerning. For these reasons, tocilizumab may not prove to be a first-line drug for RA treatment, but will likely carve out its own niche for use in the right subset of patients.