Key ACTEMRA/RoACTEMRA publication summaries
Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study
Nishimoto N, Yoshizaki K, Maeda K, Kuritani T, Deguchi H, Sato B, Imai N, Suemura M, Kakehi T, Takagi N, Kishimoto T.
J Rheumatol 2003; 30:1426–1435.
This study was an open-label, dose-ascending trial to evaluate the safety and pharmacokinetics of multiple infusions of MRA (subsequently named tocilizumab and referred to as TCZ here) in patients with active RA (N=15). Patients were assigned to receive TCZ 2, 4 or 8 mg/kg bi-weekly for 6 weeks for pharmacokinetic analysis, with treatment continuing for a total of 24 weeks to assess safety and efficacy (five patients per dose).
Key study results are summarised below.
- The half-life (t½) of tocilizumab increased with repeated doses and as the dose increased.
- At Week 2, C-reactive protein (CRP) levels and erythrocyte sedimentation rates were significantly reduced from baseline in all TCZ groups and were further improved by Week 24.
- In the TCZ 8 mg/kg group, CRP levels were normalised 2 weeks after the initial TCZ dose.
- Other measures, including swollen joint counts, tender joint counts and other acute-phase proteins (serum amyloid A, fibrinogen), were also improved by Week 24.
- Nine of 15 patients (60%) at Week 6 and 13 of 15 patients (87%) at Week 24 achieved an ACR20 response.
- At Week 24, 33% and 13% achieved an ACR50 and ACR70 response, respectively.
- Treatment tolerance of TCZ was good: at Week 24, the number of adverse events in the TCZ 2, 4 and 8 mg/kg groups were 37, 20 and 13, respectively.
- No serious adverse events were reported.
In conclusion, treatment with multiple infusions of TCZ was safe and normalised measures of acute-phase response in patients with RA. With repeated infusions, TCZ was found to accumulate in patients’ sera, prolonging the t½ at all doses. Although this study was not aimed at defining a dosing schedule, these findings indicated that increasing the interval time between TCZ infusions would be possible.