Efficacy and safety of olokizumab in patients with moderate-to-severe rheumatoid arthritis, previous exposed to anti-TNF therapy

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SCIENCE
Efficacy and safety of olokizumab in patients with moderate-to-severe rheumatoid arthritis, previous exposed to anti-TNF therapy
Key Take-Away: 

Olokizumab (OKZ), has been demonstrated to provide significant reduction in sign and symptoms of patients with moderate to severe RA, who had previously failed anti-TNF therapy and also no new safety signals were identified for OKZ.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease, which can lead to destruction, deformation and dysfunction of affected joints. Moderate-to-severe RA is often treated with disease-modifying anti-rheumatic drugs (DMARDs), with methotrexate (MTX) being the most commonly used. For patients with an inadequate response to conventional DMARDs, biologic agents which target components of the inflammatory pathway, such as tumor necrosis factor alpha (TNFa), are indicated, often in conjunction with MTX but they show inadequate responses in 40-50% patients. 

ABSTRACT: 
Background: 

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease, which can lead to destruction, deformation and dysfunction of affected joints. Moderate-to-severe RA is often treated with disease-modifying anti-rheumatic drugs (DMARDs), with methotrexate (MTX) being the most commonly used. For patients with an inadequate response to conventional DMARDs, biologic agents which target components of the inflammatory pathway, such as tumor necrosis factor alpha (TNFa), are indicated, often in conjunction with MTX but they show inadequate responses in 40-50% patients.

IL-6 plays a key role in several mechanisms underlying RA and forms an attractive alternative target for biologic therapies. Tocilizumab (TCZ), a humanized monoclonal antibody targeting the IL-6 receptor (IL-6R), has been approved for the treatment of RA. Another biologic therapy currently in development is OKZ, a humanized immunoglobulin (Ig) G4 monoclonal antibody (Mab) specific for the IL-6 cytokine. In patients with RA receiving MTX, single-dose subcutaneous administration of OKZ markedly reduced free IL-6 levels and C - reactive protein (CRP) was shown to be suppressed up to 12 weeks following treatment.

Rationale behind research

  1. Forty to fifty percent of the patients receiving anti-TNFs shows inadequate responses to such treatment
  2. Thus, there is an unmet need for new therapeutic approaches utilizing alternative modes of action in this patient population
  • Objective

To assess the efficacy and safety of OKZ, a humanized anti-interlukin 6 monoclonal antibody in patients with moderately to severely active RA patients who had previously failed anti-TNF therapy

Methods: 

 

NOTE: This phase II, dose ranging, double blind, placebo controlled, randomized study consisted of 12-week double blind phase and a 12-week safety follow-up.

  • Study outcomes
  • Primary outcomes: Change from baseline in Disease Activity Score 28-joint count (DAS28) C-reactive protein (CRP) at week 12 for 4-week cumulative dose of OKZ and placebo
  • Secondary outcomes: Week 12 American college of Rheumatology (ACR) ACR20/ACR 50/ ACR 70 response rates
  • Time Points
  • Primary outcomes: Baseline and week 12
  • Secondary outcomes: Baseline and week 12

Side effects

  • Adverse events: Baseline and week 12
Results: 

  • Outcomes
    • Baseline: At baseline, disease characteristics were generally similar between treatment groups
    • Primary Outcomes:
      • At week 12, greater improvements in least squares (LS) mean change from baseline in DAS28(CRP) were observed in all OKZ 4-week cumulative dose groups (60mg, 120 mg, 240mg), compared to the patients receiving placebo; (LS mean change from baseline: (-2.18) – (-2.68) for patients receiving OKZ; -0.64 for patients receiving placebo
      • The overall dose-response trend for the 4-week cumulative dose was statistically significant (p<0.0001), as were comparisons of each 4-week cumulative dose group versus placebo (p<0.0001 for each comparison).Figure 1: Mean change from baseline in DAS28 (CRP) at week 12 in patients by 4-week cumulative dose groups

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  • Secondary Outcomes:
    • At week 12, ACR20/ACR50 response rates were higher in all OKZ cumulative dose groups versus PBO {58.7-73.8% compared to 21.9% for ACR20, 35.7-42.1% compared to 8.6% for ACR50 (p<.05)}
    • Only few patients were ACR70 responders at week 12 and no significance was calculated for the overall dose response trend. Numerically, greater ACR70 response rates were achieved in all OKZ treatment groups compared with placebo
    • Incidence of adverse events were similar across OKZ 4-week cumulative dose groups (76.9-84.4%) and placebo (82.8%) with no deaths

Figure 2: ACR20, ACR50 & ACR70 response rates at week 12 in patients by 4-week cumulative dose groups

Conclusion: 

Study shows that OKZ is effective in improving the signs and symptoms of moderately to severely active RA in patients, previously failed anti-TNF therapy.

The safety results of this study were consistent with the safety profile expected of this class of drug. No new safety signals were identified. The results here add to the growing body of evidence surrounding the use of alternative therapeutic targets such as IL-6 in RA, in particular in patients who fail to respond adequately to anti-TNFs, and further supports the development of OKZ.

Mod Rheumatol. 2016 Jan;26(1):15-23
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