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Olokizumab versus Placebo or Adalimumab in Rheumatoid Arthritis

List of authors.
  • Josef S. Smolen, M.D.,
  • Eugen Feist, M.D.,
  • Saeed Fatenejad, M.D.,
  • Sergey A. Grishin, M.D., Ph.D.,
  • Elena V. Korneva, M.D., Ph.D.,
  • Evgeniy L. Nasonov, M.D.,
  • Mikhail Y. Samsonov, M.D., Ph.D.,
  • and Roy M. Fleischmann, M.D.
  • for the CREDO2 Group*

Abstract

Background

The cytokine interleukin-6 is involved in the pathogenesis of rheumatoid arthritis. Olokizumab, a humanized monoclonal antibody targeting the interleukin-6 cytokine directly, is being tested for the treatment of rheumatoid arthritis.

Methods

Download a PDF of the Research Summary.

In a 24-week, phase 3, multicenter, placebo- and active-controlled trial, we randomly assigned (in a 2:2:2:1 ratio) patients with rheumatoid arthritis and an inadequate response to methotrexate to receive subcutaneous olokizumab at a dose of 64 mg every 2 or 4 weeks, adalimumab (40 mg every 2 weeks), or placebo; all patients continued methotrexate therapy. The primary end point was an American College of Rheumatology 20 (ACR20) response (≥20% fewer tender and swollen joints and ≥20% improvement in three of five other domains) at week 12, with each olokizumab dose tested for superiority to placebo. We also tested the noninferiority of each olokizumab dose to adalimumab with respect to the percentage of patients with an ACR20 response (noninferiority margin, −12 percentage points in the lower boundary of the 97.5% confidence interval for the difference between groups).

Results

A total of 464 patients were assigned to receive olokizumab every 2 weeks, 479 to receive olokizumab every 4 weeks, 462 to receive adalimumab, and 243 to receive placebo. An ACR20 response at week 12 occurred in 44.4% of the patients receiving placebo, in 70.3% receiving olokizumab every 2 weeks (difference vs. placebo, 25.9 percentage points; 97.5% confidence interval [CI], 17.1 to 34.1), in 71.4% receiving olokizumab every 4 weeks (difference vs. placebo, 27.0 percentage points; 97.5% CI, 18.3 to 35.2), and in 66.9% receiving adalimumab (difference vs. placebo, 22.5 percentage points; 95% CI, 14.8 to 29.8) (P<0.001 for the superiority of each olokizumab dose to placebo). Both olokizumab doses were noninferior to adalimumab with respect to the percentage of patients with an ACR20 response at week 12 (difference, 3.4 percentage points [97.5% CI, −3.5 to 10.2] with olokizumab every 2 weeks and 4.5 percentage points [97.5% CI, −2.2 to 11.2] with olokizumab every 4 weeks). Adverse events, most commonly infections, occurred in approximately 70% of the patients who received olokizumab. Antibodies against olokizumab were detected in 3.8% of the patients receiving the drug every 2 weeks and in 5.1% of those receiving it every 4 weeks.

Conclusions

In patients with rheumatoid arthritis who were receiving maintenance methotrexate, olokizumab was superior to placebo and noninferior to adalimumab in producing an ACR20 response at 12 weeks. Larger and longer trials are required to determine the efficacy and safety of olokizumab in patients with rheumatoid arthritis. (Supported by R-Pharm; CREDO2 ClinicalTrials.gov number, NCT02760407.)

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Funding and Disclosures

Presented in part at the annual meeting of the American College of Rheumatology 2021 and the British Society for Rheumatology Conference 2021.

Supported by R-Pharm.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank all the patients who participated in the trial, and Sofia Kuzkina (R-Pharm) for medical writing assistance with an earlier version of the manuscript.

Author Affiliations

From the Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna (J.S.S.); Helios Fachklinik Vogelsang-Gommern, Vogelsang-Gommern, Germany (E.F.); SFC Medica, Charlotte, NC (S.F.); R-Pharm (S.A.G., E.V.K., M.Y.S.), V.A. Nasonova Research Institute of Rheumatology (E.L.N.), and Sechenov Medical University (M.Y.S.) — all in Moscow; and the University of Texas Southwestern Medical Center at Dallas and Metroplex Clinical Research Center — both in Dallas (R.M.F.).

Dr. Smolen can be contacted at or at the Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.

The CREDO2 Group investigators are listed in the Supplementary Appendix, available at NEJM.org.

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